ANDREAS ALONSO (2004) Proteiinityrosiinifosfataasiperheitä neljä ja taustageenejä 107 ( Pohdittavanani oleva artikkeli)

https://www.ncbi.nlm.nih.gov/pubmed/15186772

Cell. 2004 Jun 11;117(6):699-711. Protein tyrosine phosphatases in the human genome.Alonso A¹, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T.

Program of Signal Transduction, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Abstract

Tyrosine phosphorylation is catalyzed by protein tyrosine kinases (TKs), which are represented by 90 genes in the human genome.
Here, we present the set of 107 genes in the human genome that encode members of the four protein tyrosine phosphatase (PTP) families.
The four families of PTPases, their substrates, structure, function, regulation, and the role of these enzymes in human disease will be discussed.

PMID:

15186772

DOI:

10.1016/j.cell.2004.05.018

Main Text

 Introduction

Tyrosine phosphorylation is a fundamental mechanism for numerous important aspects of eukaryote physiology, as well as human health and disease (Hunter 1987 , Mustelin et al. 2002a,Mustelin et al. 2002b). Compared to protein phosphorylation in general, phosphorylation on tyrosine is extensively utilized only in multicellular eukaryotes. Tyrosine phosphorylation is used for communication between and within cells, the shape and motility of cells, decisions to proliferate versus differentiate, cellular processes like regulation of gene transcription, mRNA processing, and transport of molecules in or out of cells. Tyrosine phosphorylation also plays an important role in the coordination of these processes among neighboring cells in embryogenesis, organ development, tissue homeostasis, and the immune system. Abnormalities in tyrosine phosphorylation play a role in the pathogenesis of numerous inherited or acquired human diseases from cancer to immune deficiencies.

Although it is generally agreed that tyrosine phosphorylation is regulated by the equal and balanced action of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), proportionately much more research has focused on PTKs. This is partly for historical reasons: the first PTP was purified (Charbonneau et al., 1989) and cloned (Guan et al., 1990) ten years after the first PTK (Czernilofsky et al., 1980). Recent findings have now led to the emerging recognition that PTPs play specific and active, even dominant, roles in setting the levels of tyrosine phosphorylation in cells and in the regulation of many physiological processes (Fischer et al. 1991,Walton and Dixon 1993,Tonks and Neel 1996,Mustelinetal. 2002a,Mustelin et al. 2002b,Mustelin and Taskén 2003).

An important step toward a better appreciation of the PTPs is the clarification of the set of genes in the human genome that encode PTPs. This knowledge will allow for a more global approach to key questions in the PTP field and the regulation of tyrosine phosphorylation-dependent cellular processes in health and disease.

 The 107 Human PTP Genes

Starting with the amino acid sequence of all published PTPs, we used conserved catalytic motifs and whole PTP domains to search the publicly available databases, as well as the SEED database, for genes encoding PTPs or PTP-like genes. Two of our novel PTPs were also found in the Celera and Incyte databases. The genomic locus, exon-intron structure, expression data, and mouse orthologs were clarified for each PTP.

 Previously unpublished PTPs were subjected to a more thorough investigation to verify that they represented bona fide expressed genes with orthologs in the mouse and other organisms.

 Many of these genes have also recently been experimentally verified in our laboratories. The results of this work are a list (Table 1) of all genes in the human genome that encode PTP family members, here defined as all known protein tyrosine phosphatases plus all proteins that contain a domain homologous to the catalytic domain of these known PTPs.

 The list contains 107 genes, 105 of which have a mouse ortholog (one of the missing genes has a rat ortholog). In addition, we estimate that there are at least as many PTP pseudogenes and there are a few bona fide genes (e.g., paladin, KIAA1274) that encode proteins that contain incomplete or distant PTP-like domains. 

Of the 107 human genes, 106 are covered by expressed sequence tags (ESTs). The only gene lacking EST coverage is DUSP27 (DUPD1), which earlier was predicted to encode a phosphatase with an N-terminal cyclophilin-like domain. 

We have been able to amplify a partial cDNA of this gene from testis and muscle mRNA, demonstrating that this gene, too, is expressed. DUSP27 has four exons and is located at 10q22.3 adjacent to DUSP13 at 10q22.2, which in fact consists of two phosphatase genes, which we designate as DUSP13A and DUSP13B (encoding BEDP and TMDP, respectively), which are similar to the catalytic domain of DUSP27. In the mouse genome, the corresponding location on chromosome 14 also contains three PTP genes in tandem, although the sequence of DUSP27 is incomplete. In the chimpanzee genome, there is also a DUSP27 gene, which is 99% identical to the human within the four exons, but differs in the length of some introns. Thus, it appears that an ancestral gene was triplicated (or duplicated twice) before mice and primates diverged during the Cretaceous, 144–165 million years ago.

Table 1The Set of PTP Genes in the Human Genome

Includes all known PTPs in the published literature, verified PTPs or dual-specificity phosphatases in public data bases, and ORFs found by iterative BLAST searches with all the other sequences to find related genes and to assign alternatively spliced forms to the correct genes. To exclude synonyms, splice variants, and incorrectly assembled sequences, a data base with the amino sequences was created. To exclude pseudogenes, EST and other expression data bases were consulted, and the exon-intron structures and chromosomal locations of every gene were determined.

a the human DUSP13 gene contains two DSP genes: DUSP13A (BEDP; 3 exons), two noncoding exons, followed by DUSP13B (TMDP; three exons). In the mouse, the two genes are designated as separate genes.

b formerly DUPD1, but does not contain an N-terminal cyclophilin domain, as originally annotated. The mouse ortholog also lacks cyclophilin domain. Thus, the name DUPD1 is a misnomer.

c we have verified its expression by PCR amplification of a partial cDNA.

d there is a rat homolog, suggesting that a mouse homolog probably does exist.

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While the 38 classical PTPs have all been published (reviewed in

Andersen et al. [2004]), as many as nine of the 107 human PTP genes have not been previously reported (Supplemental Table S1 at http://www.cell.com/cgi/content/full/117/6/699/DC1), although their genomic loci, exon/intron structure, and, in most cases, their homology to PTPs were recognized in databases. These genes include six small phosphatases, DUSP15, DUSP27 (DUPD1), and four genes for which we propose the genomic designations DUSP23, DUSP24, DUSP25, and DUSP26. The protein encoded by DUSP15 is a catalytically active PTP we term VHY (VH1-related member Y;Alonso et al., 2004), closely related to VHX encoded by DUSP22. The 150 amino acid residue VHZ (VH1-related member Z) encoded by DUSP25 is the smallest of all catalytically active PTPs (

Alonso et al., 2004) and is remarkably well conserved through evolution and even has a 147 amino acid homolog in Thermococcus kodakaraensis, which is 30.3% identical and 49.7% similar over 145 residues. We have verified the existence of a 16 kDa VHZ protein in human cells by immunoblotting. The novel PTPs also include two myotubularin-related proteins, for which we propose the genomic designation MTMR14 and MTMR15. The former is the human ortholog of the Sarcophaga peregrina egg-derived tyrosine phosphatase (Yamaguchi et al., 1999) and the Drosophila melanogaster gene jumpy (Seroude et al., 2002), the mutation of which causes a muscle defect characterized by excessive vibrations of the flight muscles (J.D. and M.J. Wishart, unpublished observation). MTMR15 encodes a catalytically inactive member of the myotubularin group.

 Why So Many PTPs?

The number of genes in the human genome that encode members of the PTP families is higher than anticipated and exceeds the number of genes encoding PTKs (Manning et al., 2002). However, a direct comparison of the two numbers, 107 and 90, respectively, is not completely fair: of the 107 PTP genes,

11 are catalytically inactive, 

2 dephosphorylate mRNA, and

13 dephosphorylate inositol phospholipids. 

Thus, 81 PTPs are active protein phosphatases with the ability to dephosphorylate phosphotyrosine. 

Of the 90 PTKs tyrosine kinases), 85 are through to be catalytically active. Thus, the numbers of active PTPs and PTKs are very similar and one can therefore assume that they have comparable substrate specificities. 

Both types of enzymes also display comparable tissue distribution patterns, from ubiquitous to cell type restricted, so that individual cells express 30%–60% of the entire complement of PTPs and PTKs.

 Neuronal and hematopoietic cells may express even higher portions of all PTPs. That individual PTPs have nonredundant functions is also well illustrated by the unique phenotypes of many of the reported gene deletions in mice. For example, deletion of PTPN22 (PTPN8 in the mouse) causes excessive expansion of memory T lymphocytes, prolonged secondary immune responses, and autoimmunity (Hasegawa et al., 2004). A polymorphism in the human PTPN22 gene also correlates with autoimmune diabetes in humans (Bottini et al., 2004). Other human diseases caused by mutations in PTP genes (see discussion below) also support the notion that individual PTPs have unique and important functions.

 Classification of the 107 PTPs into Four Families

Based on the amino acid sequences of their catalytic domains, the PTPs can be grouped into four separate families, each with a range of substrate specificities (Figure 1).

Class I cysteine-based PTPs constitute by far the largest family and contain the 38 well-known “classical” PTPs (Andersen et al., 2004), which are strictly tyrosine specific and all have mouse orthologs, and the 61 VH1-like, “dual-specific” protein phosphatases (DSPs), which is the most diverse group in terms of substrate specificity (Figure 1). All Class I enzymes have evolved from a common ancestor, based upon their similar structural folds for classical PTPs, DSPs, and other VH1-like enzymes. 

The single class II cysteine-based PTP in humans is a tyrosine-specific low Mr enzyme, the origin of which appears to be more ancient than class I PTPs: representatives of this family are found in a all major phyla, including plants, numerous prokaryotes, and archea. Class II PTPs are structurally related to bacterial arsenate reductases. 

  Class III cysteine-based PTPs are tyrosine(Y)/threonine(T)-specific phosphatases that most likely evolved from a bacterial rhodanese-like enzyme. They are only represented by the three p80^Cdc25 cell cycle regulators. Interestingly, a group of class I PTPs contain a catalytically inactive rhodanese-like domain, referred to as the CDC25 homology (CH2) domain.

 Despite similarities in catalytic mechanism (Guan and Dixon, 1991) and active site structure (Barford et al. 1994,Yuvaniyama et al. 1996, Su et al. 1994,Fauman et al. 1998), class I, II, and III cysteine-based PTPs evolved independently. Nevertheless, a structural comparison indicates that they may have originated from an ancestral fold by rearrangment of elements.

 In contrast, the fourth family of PTPs use a different catalytic mechanism with a key aspartic acid(D)  and dependence on a cation. This family contains the Eya proteins, which were recently discovered to be tyrosine(Y)-, or dual serine (SS)- and tyrosine(Y)-specific protein phosphatases (

Tootle et al. 2003, Rayapureddi et al. 2003, Li et al. 2003). Determination of the substrate specificities of the large family of hydrolases to which the Eya PTPs belong will require extensive analysis. Here, only the four Eya proteins are included because they were shown experimentally to be PTPs.

 Class I Cysteine-Based PTPs

The 99 class I cysteine-based family of PTPs can be further classified into several subfamilies based on domain architecture and the degree of homology between catalytic domains. The 38 strictly tyrosine-specific “classical PTPs” can be divided into transmembrane, receptor-like enzymes (RPTPs), and the intracellular, nonreceptor PTPs (NRPTPs). They are represented in the human genome by 21 and 17 genes, respectively (Andersen et al., 2004). As is the case for the protein kinases, the number of PTP catalytic domains encoded by the genome is greater than the number of PTP genes because many of the RPTPs have tandem catalytic domains.

 The 61 VH1-like enzymes are much more diverse and can be divided into several subgroups, which share much less sequence identity with each other than the RPTPs do with the NRPTPs. Eleven of the 61 VH1-like PTPs ( MKPs)encoded by the human genome are specific for the mitogen-activated protein (MAP) kinases Erk, Jnk, and p38 (

Alonso et al. 2003a,Keyse 1998, Saxena and Mustelin 2000). These MAP kinase phosphatases (MKPs) are characterized by dual phosphothreonine and phosphotyrosine specificity and the presence of a CH2 region and other MAP kinase targeting motifs (Alonso et al. 2003b,Bordo and Bork 2002). Another subgroup of DSPs, which we have referred to as the “atypical” DSPs (Alonso et al., 2003b

), includes a number of poorly characterized enzymes that lack specific MAP kinase targeting motifs and tend to be much smaller enzymes, less than 250 amino acid residues. The first DSP to be cloned, the VH1 protein from Vaccinia virus (Guan et al., 1991), is related to this group, as are the human VHR (Ishibashi et al., 1992) and a number of genes given the genomic designations DUSP11, DUS13, DUSP14, DUSP15, DUSP18, DUSP19, DUSP21, DUSP22, and others. 

While VH1 has been reported to dephosphorylate both MAP kinases and Stat1 (Najarro et al., 2001), and VHR can dephosphorylate Erk and Jnk in 293T cells (Todd et al., 1999) and T cells (Alonso et al. 2001,Alonso et al. 2003b), it appears that many of these small atypical DSP have functions unrelated to MAP kinases. A true outlier is PIR (DUSP11), which dephosphorylates mRNA (Deshpande et al., 1999).

The three slingshots (SSH1, SSH2, and SSH3) and the three PRLs (PRL-1, PRL-2, and PRL-3) are very poorly understood, while the CDC14 group, which includes KAP, is involved in dephosphorylation of the Cdk activation loop phospho-Thr and inactivation of cyclin-dependent kinases and in exit from mitosis (Visintin et al., 1998). 

Finally, the two last subgroups of DSPs, the PTENs (5 genes) and myotubularins (16 genes), have evolved to specifically dephosphorylate the D3-phosphate of inositol phospholipids (Wishart and Dixon, 2002). Enzymes with this specificity are present also in yeast. While PTEN dephosphorylates phosphatidylinositol-3,4,5-trisphosphate at the plasma membrane, the myotubularins primarily dephosphorylate phosphatidylinositol-3-phosphate on internal cell membranes (Wishart and Dixon, 2002). Both groups also contain catalytically inactive members.

 The Class II Cysteine-Based PTPs

This family is represented in the human genome by a single gene, referred to as ACP1, which encodes the 18 kDa low Mr phosphatase (LMPTP). Related class II enzymes are widely distributed in living organisms with most bacterial genomes encoding at least one member of this family, which are remarkably well conserved through evolution. For example, the human LMPTP is 31% identical to the corresponding protein in Saccharomyces cerevisiae and 39% identical to the YfkJ protein in Bacillus subtilis. Despite the paucity of tyrosine phosphorylation in prokaryotes, the bacterial class II PTPs are bona fide tyrosine-specific phosphatases and in many cases dephosphorylate tyrosine “autokinases” involved in regulation of capsule polysaccharide synthesis. This may represent the ancestral form of tyrosine phosphorylation as a mechanism by which cells sense their extracellular environment, from which receptor PTKs and the counterbalancing PTPs may have evolved. Although the human LMPTP can dephosphorylate a number of tyrosine kinases and their substrates, its physiological function is still unclear. The preservation of a class II PTP through evolution to humans and the correlation of allelic variants of LMPTP with many common human diseases (Bottini et al., 2002), such as rheumatoid arthritis, asthma, diabetes, cardiomyopathy, and Alzheimer's disease, indicate that LMPTP likely is involved in the regulation of one or several fundamental processes in cell physiology.

 The Class III Cysteine-Based PTPs

These rhodanese-derived PTPs comprise three cell cycle regulators, CDC25A, CDC25B, and CDC25C, in humans. Their function is to dephosphorylate Cdks at their inhibitory dually phosphorylated N-terminal Thr-Tyr motifs, a reaction that is required for activation of these kinases to drive progression of cells through the cell cycle (

Honda et al., 1993). CDC25s are themselves regulated by phosphorylation. It is curious that a unique type of PTP evolved to serve regulation of the cell cycle, instead of class I or class II enzymes, which presumably already existed at the time. Interestingly, the budding yeast cell cycle can function in the absence of Cdc28 Tyr-15 phosphorylation, and so this layer of regulation may have been a later addition. In other words, CDC25 appears to have entered cell cycle regulation hand in hand with tyrosine phosphorylation of the Cdks. Alternatively, it is possible that an ancestral CDC25 already acted as a rhodanese-type enzyme on Cdks and was transformed into a phosphatase when Cdk tyrosine/threonine phosphorylation evolved. This possibility would better explain why CDC25, rather than an existing PTP, was utilized.

 Asp-Based PTPs

We have listed only the four Eya genes as members of the Asp-based PTPs because they have recently been shown to have Tyr/Ser phosphatase activity (Tootle et al. 2003,Rayapureddi et al. 2003,Li et al. 2003). It is clear that this is a much larger family of enzymes, which play important roles in development (Tootle et al. 2003,Rayapureddi et al. 2003,Li et al. 2003,Satow et al. 2002), sodium stress in yeast (Siniossoglou et al., 2000), and nuclear morphology (Siniossoglou et al., 1998). RNA polymerase II C-terminal domain phosphatase is also a member of this family. However, a clear and structurally based definition of this family of enzymes will be needed before the human gene complement of Asp-based phosphatases can be more accurately determined.

 Modular Structure of PTPs

One of the most striking features of the PTP families (Figure 2) is that most enzymes consist of combinations of modular domains. At least 79 of the 107 PTPs contain at least one additional motif or domain (Table 2) outside of their catalytic PTP domain. Many of the domains are protein-protein interaction or phospholipid binding modules. In this respect, PTPs resemble the PTKs (

Manning et al., 2002), but they differ markedly from the serine/threonine-specific protein phosphatases. In PTKs, protein-protein interaction domains serve two distinct purposes: regulation and targeting to substrates and/or subcellular compartments. This appears to be the case also for PTPs, although many of the domains in PTPs are still poorly understood. The set of domains found in PTPs are listed in Table 2 and they include domains that bind specific domains or motifs in other proteins (unphosphorylated or phosphorylated), cellular membranes, the cytoskeleton, or specific phospholipids.

It is interesting to note that the set of protein domains found in PTPs is only partly overlapping with those found in PTKs (Manning et al., 2002). While many PTKs have SH3 and SH2 domains, often in combinations, such as SH3-SH2 or SH2-SH2, only two human PTPs (SHP1 and SHP2) have SH2 domains organized in a tandem fashion like in the Syk family PTKs. Also, the catalytically inactive PTEN-related tensin and C1-TEN have an SH2 domain adjacent to a PTB domain. In contrast, there are no PTPs with SH3 domains. Conversely, there are no known kinases with CRAL/TRIO (Sec14p homology), rhodanese, FYVE, or mRNA capping domains. Nevertheless, it is interesting to note that different domains may serve similar functions in PTPs compared to PTKs. For example, while PTKs mostly use PH domains to interact with phosphoinositides, PTPs use CRAL/TRIO (

Huynh et al., 2003) and FYVE domains for the same purpose. Only the myotubularins have PH domains, but it is unclear if they function to interact selectively with phospholipid since myotubularins mostly do not localize to the plasma membrane. In fact, the PH domain of myotubularins was referred to as a GRAM domain until the crystal structure of MTMR2 (

Begley et al., 2003) showed that this region folds as a PH domain.

PTPs also use FERM domains to direct them to the cytoskeleton/plasma membrane interface in a phosphoinositide-dependent manner, analogous to the use of SH3, PH, and C2 domains by kinases. FERM domains may also be able to bind phosphotyrosine, and PTPs may use catalytically inactive PTP (“STYX”) domains in a SH2-like manner to interact with tyrosine phosphorylated proteins (Wishart and Dixon, 1998). Together, these differences in domain structure between PTPs and PTKs may reflect the need to regulate these two classes of enzymes in temporally and spatially distinct and often reciprocal manners.

 Hints of Function from the Multidomain Architecture

RPTPs

In many PTPs, the nature of their extracatalytic domains gives some indications as to subcellular location or function. For example, all transmembrane classical PTPs have a membrane-spanning α helix (by definition) and are located in cellular membranes, mostly the plasma membrane, where they interact with the extracellular milieu in a receptor-like fashion. All but RPTPα and RPTPϵ have extended extracellular portions with immunoglobulin, fibronectin, MAM, and carbonic anhydrase domains. Another example is laforin, a PTP that is mutated in an inherited form of progressive myoclonus epilepsy (Lafora's disease;Minassian et al., 1998), characterized histologically by accumulation of glycogen-containing granules in the cytoplasm of cells. Recently, laforin was shown to contain a glycogen binding domain, implying a direct role for laforin in glycogen metabolism (

Wang et al., 2002).

 The 17 nonreceptor classical PTPs are particularly rich in protein-protein interaction domains and many of them have several such domains. Within this group, SHP1 and SHP2 provide a good example of how protein-protein interaction domains can cooperate with a PTP domain to achieve both intramolecular regulation and targeting to substrates. In the absence of ligands for the tandem SH2 domain of these PTPs, the more N-terminal SH2 domain folds onto the catalytic domain to block substrate access by the insertion of a loop on the backside of the SH2 domain into the catalytic pocket of the PTP (Hof et al., 1998). When the SH2 domains of this inhibited form of SHP1 or SHP2 encounter a tyrosine phosphorylated ligand, the closed conformation opens and the enzyme is activated some 100-fold (Pei et al. 1994,Pluskey et al. 1995). Under physiological conditions, SH2 domain ligand binding also juxtaposes the PTP domain to its substrates, which contain, or associate with, the phosphorylated SH2 domain ligand.

The DSP subfamily contains 11 members with a CH2 domain, a region derived from the bacterial rhodanese enzyme and adapted to a MAP kinase docking motif (Alonso et al. 2003b,

Bordo and Bork 2002). In CDC25, on the other hand, the rhodanese has evolved into a catalytic PTP domain (Bordo and Bork, 2002). Other noncatalytic domains and motifs found in DSPs include FYVE, glycogen binding, mRNA capping (guanyl methyltransferase), and consensus recognition motifs for N-terminal myristylation or C-terminal prenylation. PTEN contains a C2 domain tightly packed against the PTP domain, while members of the myotubularin family contain PH, FYVE, coiled-coil, and PDZ binding motifs (Wishart and Dixon, 2002). A number of additional protein-protein interaction domains are found in PTPs in other organisms, for example a WW domain in a C. elegans PTP (Sudol, 1996), but are not present in the human PTPs either because they have been lost or because they evolved in a separate lineage.

 Large Multidomain PTPs versus Multisubunit Ser/Thr Phosphatases

The multidomain structure of most PTPs is in sharp contrast to the serine/threonine protein phosphatases, which generally consist of small catalytic subunits that bind regulatory or targeting subunits encoded by separate genes to form a large number of distinct holoenzymes with different biological functions. This dichotomy may explain the differences in gene numbers: 107 PTPs to counteract 90 PTKs versus many fewer catalytic Ser/Thr phosphatase subunits to counter 428 protein kinases and the extensive phosphorylation of more than a third of all cellular proteins. Presumably, the combinatorial subunit principle of serine/threonine protein phosphatases can generate much more diversity and flexibility, but may lack some of the strict specificity and tight regulation possible with single-chain multidomain PTPs. In this context, it may also be significant that the atypical DSP subgroup of PTPs contains many small enzymes devoid of other domains or motifs. It is possible that these enzymes participate in multisubunit complexes where other subunits provide regulation and substrate targeting. However, no examples of this have yet been found.

 Catalytically Inactive PTP Domains

Among the class I cysteine-based PTPs, there are at least 14 catalytically inactive PTP domains, in which critical catalytic residues have been altered. These are the second (D2) domains of CD45, RPTPγ, and RPTPζ, and the only PTP domains of the secretory vesicle-located receptor-like PTP IA-2 (Solimena et al., 1996), a VHR-like protein termed STYX (Wishart et al., 1995), the MKP-like MK-STYX (Wishart and Dixon, 1998), the PTEN-related tensin and C1-ten, and the myotubularin-related proteins MTMR5, MTMR9, MTMR11, MTMR12, MTMR13 (Wishart and Dixon, 2002), and MTMR15. Despite lack of catalytic activity, many of these proteins still play important roles in cells, in many cases by partnering with active PTPs. For example, CD45 needs its inactive D2 domain for dephosphorylation by D1 of its physiological substrates (Kashio et al., 1998). Similarly, the inactive MTMRs seem to act as important regulatory subunits for active members of the group, as shown by the human disease Charcot-Marie-Tooth type 4B, which is caused by mutation of the catalytically active MTMR2 (Bolino et al., 2000) or the catalytically inactive MTMR13 (

Azzedine et al., 2003), in both cases with identical pathology and symptoms. It turns out that these two proteins form a heterodimer, in which the activity of MTMR2 depends on MTMR13. There are similar examples where an inactive kinase domain is needed to activate a catalytically competent kinase domain; e.g., LKB1 is activated by STRAD (Baas et al., 2003). In addition to these inherently inactive PTP domains, alternative splicing of PTP transcripts (which occurs in at least half of all PTPs) can create isoforms that have catalytically inactive PTP domains (Tailor et al., 1999

), or lack them altogether (Bult et al., 1997). 

Physiologically important alternative splicing within the catalytic domains is known to create two isoforms of the class II enzyme LMPTP with different specific activity, substrate specificity, and regulation (Mitchell Bryson et al., 1995). In this enzyme, the ratio of the two isoforms is genetically determined and subject to allelic variation, which correlates with the predisposition to several common human diseases (Bottini et al., 2002).

 Posttranslational Modifications and Reversible Oxidation of PTPs

The majority of PTPs are posttranslationally modified. Glycosylation appears to be restricted to the transmembrane PTPs, which contain abundant N- and O-linked carbohydrates in their extracellular portions. 

Two groups of DSPs are modified by fatty acids: VHY (DUSP15) and VHX (DUSP22) are N-terminally myristylated in a manner reminiscent of Src family PTKs (

Alonso et al., 2004), while the PRLs are C-terminally farnesylated similar to Ras GTPases. By far the most common modification is the phosphorylation of PTPs on serine, threonine, and tyrosine. There are many examples where Ser/Thr phosphorylation has been shown to regulate activity. The phosphorylation of PTPs on tyrosine is particularly intriguing as it implies a physical, if not functional, interaction with PTKs (Mustelin and Hunter, 2002). At least 15 PTPs have been reported to be tyrosine phosphorylated, but the physiological significance remains unclear in most cases. Tyrosine phosphorylation also introduces the possibility of autodephosphorylation. In fact, many PTPs become noticeably more phosphorylated on tyrosine when expressed as catalytically inactive mutants. In most cases, however, the phosphorylation sites are clearly inaccessible for intramolecular dephosphorylation, suggesting that dephosphorylation must occur in trans. Thus, regulatory networks of PTPs and other protein phosphatases, perhaps in the form of “phosphatase cascades,” may exist in cells.

It has been known for many years that the catalytic cysteine of class I and II PTPs is highly susceptible to oxidation in vitro, and it has been speculated that this could play a role in intact cells exposed to oxidizing agents. An exciting new development was the discovery that oxidation of PTP1B does not result in a stable sulfenic acid derivative of the catalytic site cysteine, but rapidly transforms into a sulfenyl amide ring involving the adjacent serine residue (Salmeen et al. 2003,

van Montfort et al. 2003). This form is resistant to further oxidation, which would be irreversible, and is readily reduced back to the free cysteinyl, catalytically active form. Together with recent insights into the production of reactive oxygen species and nitrogen oxides in cells during growth factor stimulation in cancer, inflammation, and neurodegenerative diseases, it now seems likely that reversible redox regulation of PTPs occurs in intact cells. Since PTPs often play dominant roles in setting the levels of tyrosine phosphorylation in cells, this regulation may be physiologically very important.

PTPs as Drug Targets

Compared to the PTKs, many inhibitors (TKI) of which already are in clinical trials, the PTPs are newcomers in the field of drug development. The effect of disruption of the PTP1B gene in mice, which indicated that this PTP acts as a negative regulator of insulin signaling (Elchebly et al., 1999), ignited the interest of the pharmaceutical industry. Recent discoveries that many other PTPs also play critical roles in a variety of human disease (Table 3) have sparked a growing interest in PTPs as drug targets. In addition to metabolic, neurological, muscle, and autoimmune diseases, at least 30 PTPs have been implicated in cancer (listed inAndersen et al. [2004]). We expect that with improved understanding of the molecular mechanisms by which PTPs affect the pathophysiology of these diseases, combined with the dominant role that PTPs often play in the regulation of tyrosine phosphorylation-dependent processes, PTP inhibitors will become clinically relevant therapeutics in the future. A rational design of small-molecule inhibitors against PTPs using in silico docking, NMR-based methods, high-throughput crystallization, and specific chemistry will most likely be involved. Following initial concerns about specificity and problems associated with the hydrophilicity of phosphomimetics, promising successes have been achieved by structure-based drug design, particularly those that utilize unique features of the surface topology surrounding the catalytic pocket of each PTP. Figure 3 shows the surface topology and charge distribution of a representative set of catalytic PTP domains to illustrate the striking diversity within the class I PTPs. For example, for PTP1B it was found that a unique second PTyr binding site (Puius et al. 1997, Salmeen et al. 2000) could be used to develop highly specific bidentate inhibitors that bind both sites (Zhang, 2002). This general approach can be used to design highly specific and effective inhibitors.

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PTPRC (CD45)	SCID (Kung et al., 2000; Tchilian et al., 2001 ), multiple sclerosis ( Jacobsen et al., 2000 )

PTPRN (IA-2)	Antigen for autoimmune diabetes ( Solimena et al., 1996
PTPRN2 (phogrin)	Antigen for autoimmune diabetes Kawasaki et al., 1996
PTPN1 (PTP1B)	Insulin resistance, obesity Andersen et al., 2004
PTPN6 (SHP1)	Sezary syndrome ( Andersen et al., 2004
PTPN9 (PTP-MEG2)	Autism (Smith et al., 2000)
PTPN11 (SHP2)	Noonan syndrome Tartaglia et al., 2001
PTPN22 (LYP)	SNP polymorphism in type I diabetes Bottini et al., 2004
PTEN (PTEN)	Bannayan-Zonana (Marsh et al., 1997), Cowden syndrome and Lhermitte-Duclos disease Liaw et al., 1997
MTM1 (myotubularin)	X-linked myotubular myopathy ( Laporte et al., 1996
MTMR2 (MTMR2)	Charcot-Marie-Tooth syndrome type 4B ( Bolino et al., 2000
MTMR13 (MTMR13)	Charcot-Marie-Tooth syndrome type 4B ( Azzedine et al., 2003
EPM2A (laforin)	Progressive myoclonus epilepsy (Lafora's disease) ( Minassian et al., 1998
ACP1 (LMPTP)	Polymorphism correlates with many common diseases ( Bottini et al., 2002

107 PTP genes 

A. Class I Cys-Based PTPs (99 Genes)
A. 1. Classical PTPs (38 Genes)
A. 1. 1. Transmembrane Classical PTPs (21 Genes)
1. PTPRA	RPTPα	20p13	YES	YES
2. PTPRB	RPTPβ	12q15-q21	YES	YES
3. PTPRC	CD45, LCA	1q31-q32	YES	YES
4. PTPRD	RPTPδ	9p23-p24.3	YES	YES
5. PTPRE	RPTPϵ	10q26	YES	YES
6. PTPRF	LAR	1p34	YES	YES
7. PTPRG	RPTPγ	3p21-p14	YES	YES
8. PTPRH	SAP1	19q13.4	YES	YES
9. PTPRJ	DEP1, CD148, RPTPη	11p11.2	YES	YES
10. PTPRK	RPTPκ	6q22.2-23.1	YES	YES
11. PTPRM	RPTPμ	18p11.2	YES	YES
12. PTPRN	IA-2, Islet cell antigen 512	2q35-q36.1	YES	YES
13. PTPRN2	PTPRP, RPTPπ, IA-2β, phogrin,	7q36	YES	YES
14. PTPRO	GLEPP1/PTP-U2/PTPROτ isoforms A/B/C	12p13.3-p13.2	YES	YES
15. PTPRQ	PTPS31	12q21.31	YES	YES
16. PTPRR	PTP-SL, PCPTP,PTPBR7, PC12-PTP1	12q15	YES	YES
17. PTPRS	RPTPσ	19p13.3	YES	YES
18. PTPRT	RPTPρ	20q12-q13	YES	YES
19. PTPRU	PTPJ/PTP-U1/PTPRomicron isoforms 1/2/3	1p35.3-p35.1	YES	YES
20. PTPRV	OST-PTP	1q32.1	YES	YES
21. PTPRZ	RPTPζ	7q31.3	YES	YES
A. 1.2. NRPTPs (17 Genes),  inracellular
22. PTPN1	PTP1B	20q13.1-13.2	YES	YES
23. PTPN2	TCPTP, MPTP, PTP-S	18p11.3-11.2	YES	YES
24. PTPN3	PTPH1	9q31	YES	YES
25. PTPN4	PTP-MEG1, TEP	2q14.2	YES	YES
26. PTPN5	STEP	11p15.1	YES	YES
27. PTPN6	SHP1, PTP1C, SH-PTP1, HCP	12p12-13	YES	YES
28. PTPN7	HePTP, LCPTP	1q32.1	YES	YES
29. PTPN9	PTP-MEG2	15q23	YES	YES
30. PTPN11	SHP2, SH-PTP2, Syp, PTP1D, PTP2C, SH-PTP3	12q24.1	YES	YES
31. PTPN12	PTP-PEST, PTP-P19, PTPG1)	7q11.23	YES	YES
32. PTPN13	PTP-BAS, FAP-1, PTP1E, RIP, PTPL1, PTP-BL	4q21.3	YES	YES
33. PTPN14	PTP36, PEZ, PTPD2	1q32.2	YES	YES
34. PTPN18	PTP-HSCF, PTP20, BDP	2q21.2	YES	YES
35. PTPN20	TypPTP	10q11.22	YES	YES
36. PTPN21	PTPD1, PTP2E, PTP-RL10	14q31.3	YES	YES
37. PTPN22	LYP, PEP	1p13.3-p13.1	YES	YES
38. PTPN23	HD-PTP, HDPTP, PTP-TD14, KIAA1471, DKFZP564F0923	3p21.3	YES	YES
A. 2. DSPs or VH1-like (61 Genes) A. 2. 1. MKPs (11 Genes)
39. DUSP1	MKP-1, 3CH134, PTPN10, erp, CL100/ HVH1	5q34	YES	YES
40. DUSP2	PAC-1	2q11	YES	YES
41. DUSP4	MKP-2, hVH2/TYP1	8p12-p11	YES	YES
42. DUSP5	hVH3/B23	10q25	YES	YES
43. DUSP6	PYST1, MKP-3/rVH6	12q22-q23	YES	YES
44. DUSP7	PYST2, B59, MKP-X	3p21	YES	YES
45. DUSP8	hVH5, M3/6, HB5	11p15.5	YES	YES
46. DUSP9	MKP-4, Pyst3	Xq28	YES	YES
47. DUSP10	MKP-5	1q41	YES	YES
48. DUSP16	MKP-7, MKP-M	12p13	YES	YES
49. MK-STYX	MK-STYX	7q11.23	YES	YES
A. 2. 2. Atypical DSPs (19 Genes)
50. DUSP3	VHR, T-DSP11	17q21	YES	YES
51. DUSP11	PIR1	2p13.1	YES	YES
52. DUSP12	HYVH1, GKAP, LMW-DSP4	1q21-q22	YES	YES
53. DUSP13A a	BEDP	10q22.2	YES	YES
54. DUSP13B a	TMDP, TS-DSP6	10q22.2	YES	YES
55. DUSP14	MKP6, MKP-L	17q12	YES	YES
56. DUSP15	VHY, Q9H1R2	20q11.21	YES	YES
57. DUSP18	DUSP20, LMW-DSP20	22q12.2	YES	YES
58. DUSP19	DUSP17, SKRP1, LDP-2, TS-DSP1	2q32.1	YES	YES
59. DUSP21	LMW-DSP21, BJ-HCC-26 tumor antigen	Xp11.4-p11.23	YES	YES
60. DUSP22	VHX, MKPX, JSP1, LMW-DSP2, TS-DSP2, JKAP	6p25.3	YES	YES
61. DUSP23	MOSP, similar to RIKEN cDNA 2810004N20	11p11.2	YES	YES
62. DUSP24	MGC1136	8p12	YES	YES
63. DUSP25	VHZ, FLJ20442, LMW-DSP3	1q23.1	YES	YES
64. DUSP26	VHP, “similar to RIKEN cDNA 0710001B24”	2q37.3	YES	YES
65. DUSP27 b	DUPD1, FMDSP, “similar to cyclophilin”	10q22.3	NO c	YES
66. EPM2A	Laforin	6q24	YES	YES
67. RNGTT	mRNA capping enzyme	6q16	YES	YES
68. STYX	STYX	14	YES	YES
A. 2. 3. Slingshots (3 Genes)
69. SSH1	SSH1, slingshot 1	12q24.12	YES	YES
70. SSH2	SSH2, slingshot 2	17q11.2	YES	YES
71. SSH3	SSH3, slingshot 3	11q13.1	YES	YES
A. 2. 4. PRLs (3 Genes)
72. PTP4A1	PRL-1	6q12	YES	YES
73. PTP4A2	PRL-2, OV-1	1p35	YES	YES
74. PTP4A3	PRL-3	8q24.3	YES	YES
A. 2. 5. CDC14s (4 Genes)
75. CDC14A	CDC14A	1p21	YES	YES
76. CDC14B	CDC14B	9q22.33	YES	YES
77. CDKN3	KAP	14q22	YES	YES
78. PTP9Q22	PTP9Q22	9q22.32	YES	YES
A. 2. 6. PTENs (5 Genes)
79. PTEN	PTEN, MMAC1, TEP1	10q23.3	YES	YES
80. TPIP	TPIPα, TPTE and PTEN homologous	13q12.11	YES	YES
81. TPTE	PTEN-like, PTEN2	21p11	YES	YES
82. TNS	Tensin	2q35-q36	YES	YES
83. TENC1	C1-TEN, TENC1, KIAA1075	12q13.13	YES	YES
A. 2. 7. Myotubularins (16 Genes)
84. MTM1	myotubularin	Xq28	YES	YES
85. MTMR1	MTMR1	Xq28	YES	YES
86. MTMR2	MTMR2	11q22	YES	YES
87. MTMR3	MTMR3, FYVE-DSP1	22q12.2	YES	YES
88. MTMR4	MTMR4, FYVE-DSP2	17q22-q23	YES	YES
89. MTMR5	MTMR1, SBF1	22q13.33	YES	YES
90. MTMR6	MTMR6	13q12	YES	YES
91. MTMR7	MTMR7	8p22	YES	YES
92. MTMR8	MTMR8	Xq11.2	YES	NO
93. MTMR9	MTMR9, LIP-STYX	8p23-p22	YES	YES
94. MTMR10	MTMR10	15q13.1	YES	NO d
95. MTMR11	MTMR11CRA α/β	1q12.3	YES	YES
96. MTMR12	MTMR12, 3-PAP	5p13.3	YES	YES
97. MTMR13	MTMR13, SBF2, CMT4B2	11p15.3	YES	YES
98. MTMR14	FLJ22075, hJumpy, hEDTP	3p26	YES	YES
99. MTMR15	KIAA1018	15q13.1	YES	YES
B. Class II Cys-Based PTPs (1 Gene)
100. ACP1	LMPTP, low Mr PTP, LMWPTP, BHPTP	2p25	YES	YES
C. Class III Cys-Based PTPs (3 Genes)
101. CDC25A	CDC25A	3p21	YES	YES
102. CDC25B	CDC25B	20p13	YES	YES
103. CDC25C	CDC25C	5q31	YES	YES
D. Asp-Based PTPs (4 Genes)
104. EYA1	Eya1	8q13.3	YES	YES
105. EYA1	Eya2	20q13.1	YES	YES
106. EYA1	Eya3	1p36	YES	YES
107. EYA1	Eya4	6q23	YES	YES
107. Total

Thalamus: aspekti ALS

(1)  https://www.ncbi.nlm.nih.gov/pubmed/?term=ALS%2C+thalamus

Brain Pathol. 2018 Jan;28(1):14-27. doi: 10.1111/bpa.12467. Epub 2017 Mar 22.

Neurodegeneration and NLRP3 inflammasome expression in the anterior thalamus of SOD1(G93A) ALS mice.

Debye B¹, Schmülling L¹, Zhou L², Rune G², Beyer C¹, Johann S¹. Abstract

Nowadays, amyotrophic lateral sclerosis (ALS) is considered as a multisystem disorder, characterized by a primary degeneration of motor neurons as well as neuropathological changes in non-motor regions. Neurodegeneration in subcortical areas, such as the thalamus, are believed to contribute to cognitive and behavioral abnormalities in ALS patients. In the present study, we investigated neurodegenerative changes including neuronal loss and glia pathology in the anterodorsal thalamic nucleus (AD) of SOD1(G93A) mice, a widely used animal model for ALS. We detected massive dendrite swelling and neuronal loss in SOD1(G93A) animals, which was accompanied by a mild gliosis. Furthermore, misfolded SOD1 protein and autophagy markers were accumulating in the AD.
Since innate immunity and activation inflammasomes seem to play a crucial role in ALS, we examined protein expression of Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase-1 recruitment domain (ASC) and the cytokine interleukin 1 beta (IL1β) in AD glial cells and neurons. NLRP3 and ASC were significantly up-regulated in the AD of SOD1(G93A) mice. Finally, co-localization studies revealed expression of NLRP3, ASC and IL1β in neurons. Our study yielded two main findings: (i) neurodegenerative changes already occur at an early symptomatic stage in the AD and (ii) increased inflammasome expression may contribute to neuronal cell death. In conclusion, neurodegeneration in the anterior thalamus may critically account for cognitive changes in ALS pathology.

(2)

Front Aging Neurosci. 2018 Mar 15;10:45. doi: 10.3389/fnagi.2018.00045. eCollection 2018.

Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study. Schönecker S¹, Neuhofer C¹, Otto M², Ludolph A², Kassubek J², Landwehrmeyer B², Anderl-Straub S², Semler E², Diehl-Schmid J³, Prix C¹, Vollmar C¹, Fortea J⁴; Deutsches FTLD-Konsortium, Huppertz HJ⁵, Arzberger T⁶, Edbauer D^7,8,9, Feddersen B¹⁰, Dieterich M^1,7,9, Schroeter ML^11,12, Volk AE¹³, Fließbach K^14,15, Schneider A^14,15, Kornhuber J¹⁶, Maler M¹⁶, Prudlo J^17,18, Jahn H^19,20, Boeckh-Behrens T²¹, Danek A¹, Klopstock T^7,9,22, Levin J^1,7. Collaborators (4) Abstract

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

KEYWORDS:

C9orf72; amyotrophic lateral sclerosis; atlas based volumetric MRI analysis; cerebellum; frontotemporal dementia; salience network; thalamus

PMID:

29599716

PMCID:

PMC5863593

DOI:

10.3389/fnagi.2018.00045

Free PMC Article

 

3) 

Transl Psychiatry. 2019 Jan 31;9(1):54. doi: 10.1038/s41398-019-0381-1.

FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations.

Diehl-Schmid J¹, Licata A², Goldhardt O², Förstl H², Yakushew I³, Otto M⁴, Anderl-Straub S⁴, Beer A⁴, Ludolph AC⁴, Landwehrmeyer GB⁴, Levin J^5,6, Danek A⁵, Fliessbach K^7,8, Spottke A^8,9, Fassbender K¹⁰, Lyros E¹⁰, Prudlo J¹¹, Krause BJ¹², Volk A¹³, Edbauer D^6,14, Schroeter ML^15,16, Drzezga A^17,18, Kornhuber J¹⁹, Lauer M²⁰; FTLDc Study Group, Grimmer T².Collaborators (15)

Abstract

C9ORF72 mutations are the most common cause of familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). MRI studies have investigated structural changes in C9ORF72-associated FTLD (C9FTLD) and provided first insights about a prominent involvement of the thalamus and the cerebellum. Our multicenter, ¹⁸F-fluorodeoxyglucose positron-emission tomography study of 22 mutation carriers with FTLD, 22 matched non-carriers with FTLD, and 23 cognitively healthy controls provided valuable insights into functional changes in C9FTLD: compared to non-carriers, mutation carriers showed a significant reduction of glucose metabolism in both thalami, underscoring the key role of the thalamus in C9FTLD. Thalamic metabolism did not correlate with disease severity, duration of disease, or the presence of psychotic symptoms. Against our expectations we could not demonstrate a cerebellar hypometabolism in carriers or non-carriers. Future imaging and neuropathological studies in large patient cohorts are required to further elucidate the central role of the thalamus in C9FTLD.

PMID:

30705258

PMCID:

PMC6355852

DOI:

10.1038/s41398-019-0381-1

[Indexed for MEDLINE]

Free PMC Article

• 
  

ihmisen WIPI genejä löytyy 4 : (WD-repeat domain phosphoinostitide (PI) interacting 1-4)

Search results

Items: 4

• Showing Current items.

Name/Gene ID	Description	Location	Aliases	MIM
Select item 55062 WIPI1 ID: 55062	WD repeat domain, phosphoinositide interacting 1 [Homo sapiens (human)]	Chromosome 17, NC_000017.11 (68421281..68457524, complement)	ATG18, ATG18A, WIPI49	609224
Select item 26100 WIPI2 ID: 26100	WD repeat domain, phosphoinositide interacting 2 [Homo sapiens (human)]	Chromosome 7, NC_000007.14 (5190233..5233855)	ATG18B, Atg21, CGI-50, IDDSSA, WIPI-2	609225
Select item 11152 WDR45 ID: 11152	WD repeat domain 45 [Homo sapiens (human)]	Chromosome X, NC_000023.11 (49074433..49101121, complement)	JM5, NBIA4, NBIA5, WDRX1, WIPI-4, WIPI4	300526
Select item 56270 WDR45B ID: 56270	WD repeat domain 45B [Homo sapiens (human)]	Chromosome 17, NC_000017.11 (82614562..82648530, complement)	NEDSBAS, WDR45L, WIPI-3, WIPI3	609226

WIPI4 (xp11.23), JM5, NBIA4, NBIA5, WDRX1, WIPI-4, autofagiageeni, raudan käsittely hermostossa

Official Symbol

WDR45provided by HGNC

Official Full Name

WD repeat domain 45provided by HGNC

Also known as

JM5; NBIA4; NBIA5; WDRX1; WIPI4; WIPI-4

Summary

This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene has a pseudogene at chromosome 4q31.3. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity and full-length nature of some variants have not been determined. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in thyroid (RPKM 16.7), adrenal (RPKM 15.8) and 25 other tissues See more

Orthologs

 

Preferred Names

WD repeat domain phosphoinositide-interacting protein 4

Names

WD repeat domain, X-linked 1

WD repeat-containing protein 45

WD45 repeat protein interacting with phosphoinositides 4

neurodegeneration with brain iron accumulation 4, NDIA4

neurodegeneration with brain iron accumulation 5, NDIA5

https://www.ncbi.nlm.nih.gov/protein/NP_001025067.1

Conserved Domains (3) summary

COG2319
Location:9 → 275

WD40; WD40 repeat [General function prediction only]

sd00039
Location:196 → 232

7WD40; WD40 repeat [structural motif]

cl29593
Location:187 → 274

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from ..

 

Related articles in PubMed

1. Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants. Chen H, et al. Eur J Med Genet, 2019 Feb. PMID 29981852
2. Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45. Carvill GL, et al. Epilepsia, 2018 Jan. PMID 29171013, Free PMC Article
3. Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. Takano K, et al. Eur J Med Genet, 2017 Oct. PMID 28711740
4. Clinical features of a female with WDR45 mutation complicated by infantile spasms: a case report and literature review. Morikawa M, et al. Brain Dev, 2017 Oct. PMID 28551038
5. Beta-Propeller Protein-Associated Neurodegeneration Gregory A, et al. , 1993. PMID 28211668

See all (39) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Novel missense mutations in WDR45 were identified in female pediatric patients with developmental delay and/or epilepsy. Arg134Pro and p. Gly168Glu mutations showed accumulation of LC3-containing autophagic structures and enlarged cell volume in HeLa cells.
2. WIPI3 and WIPI4 beta-propellers have roles as scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy
3. This study showed that Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.
4. This study showed that WDR45 genes account for disease of patients diagnosed with an Neurodegeneration with brain iron accumulation disorder.
5. This study showed the WDR45 mutation complicated by infantile spasms.
6. A rare male patient is reported with mutation in WDR45 and early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase.
7. Inherited WDR45 variants are possible, albeit rare. Hemizygous germline variants in males can be viable, but likely result in a more severe NBIA phenotype.
8. Our findings indicate that hemizygous WDR45 mutations in males lead to severe epileptic encephalopathy.
9. WDR45 mutation is associated with beta-propeller protein-associated neurodegeneration.
10. Genetic analysis for WDR45 revealed that she had a splice site mutation

Submit: New GeneRIF Correction See all GeneRIFs (17)

 

WIPI3, WDR46B, (17q25.3), NEDSBAS , beeta-propellirakenteinen autofagian kotrolloija

https://www.ncbi.nlm.nih.gov/gene/56270

Official Symbol

WDR45Bprovided by HGNC

Official Full Name

WD repeat domain 45Bprovided by HGNC

Also known as

WIPI3; WDR45L; WIPI-3; NEDSBAS

Summary

This gene encodes a member of the WIPI or SVP1 family of WD40 repeat-containing proteins. The protein contains seven WD40 repeats that are thought to fold into a beta-propeller structure that mediates protein-protein interactions, and a conserved motif for interaction with phospholipids. The human genome contains several pseudogenes of this gene. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in testis (RPKM 30.3), esophagus (RPKM 20.3) and 25 other tissues See more

Orthologsmouse all

Preferred Names

WD repeat domain phosphoinositide-interacting protein 3

Names

WD repeat protein 45-like

WD repeat-containing protein 45-like

WD repeat-containing protein 45B

WDR45-like protein

WIPI3 long

WIPI49-like protein

 https://www.ncbi.nlm.nih.gov/protein/NP_062559.2

ORIGIN      
        1 mnllpcnphg ngllyagfnq dhgcfacgme ngfrvyntdp lkekekqefl eggvghveml
       61 frcnylalvg ggkkpkyppn kvmiwddlkk ktvieiefst evkavklrrd rivvvldsmi
      121 kvftfthnph qlhvfetcyn pkglcvlcpn snnsllafpg thtghvqlvd lastekppvd
      181 ipahegvlsc ialnlqgtri atasekgtli rifdtssghl iqelrrgsqa aniycinfnq
      241 daslicvssd hgtvhifaae dpkrnkqssl asasflpkyf sskwsfskfq vpsgspcica
      301 fgtepnavia icadgsyykf lfnpkgecir dvyaqflemt ddkl
//

Related articles in PubMed

1. PtdIns-specific MPR pathway association of a novel WD40 repeat protein, WIPI49. Jeffries TR, et al. Mol Biol Cell, 2004 Jun. PMID 15020712, Free PMC Article
2. WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Proikas-Cezanne T, et al. Oncogene, 2004 Dec 16. PMID 15602573
3. WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy. Bakula D, et al. Nat Commun, 2017 May 31. PMID 28561066, Free PMC Article
4. Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis. Raman M, et al. Nat Cell Biol, 2015 Oct. PMID 26389662, Free PMC Article
5. The sequence of the human genome. Venter JC, et al. Science, 2001 Feb 16. PMID 11181995

See all (17) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. WIPI3 and WIPI4 beta-propellers have roles as scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy

Submit: New GeneRIF Correction

WIPI2(7p22.1). Atg21, ATG18B, CGI-50, IDDSSA. WD-toistojaksoinen fosfoinositidin kanssa interaktion tekevä proteiini2

https://www.ncbi.nlm.nih.gov/gene/26100

Also known as

Atg21; ATG18B; CGI-50; IDDSSA; WIPI-2

Summary

WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins, such as WIPI2, have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids (Proikas-Cezanne et al., 2004 [PubMed 15602573]).[supplied by OMIM, Mar 2008]

Expression

Ubiquitous expression in testis (RPKM 20.8), brain (RPKM 12.7) and 25 other tissues See more

Orthologs mouse all

Preferred Names

WD repeat domain phosphoinositide-interacting protein 2

Names

WD40 repeat protein interacting with phosphoinositides 2

WIPI49-like protein 2

                     /db_xref="MIM:609225"
ORIGIN      
        1 mnlasqsgea gagqllfanf nqdntevkga sraaglgrra vvwslavgsk sgykffslss
       61 vdkleqiyec tdtedvcive rlfssslvai vslkaprklk vchfkkgtei cnysysntil
      121 avklnrqrli vcleeslyih nirdmkvlht iretppnpag lcalsinndn cylaypgsat
      181 igevqvfdti nlraanmipa hdsplaalaf dasgtklata sekgtvirvf sipegqklfe
      241 frrgvkrcvs icslafsmdg mflsassnte tvhifkletv kekppeeptt wtgyfgkvlm
      301 astsylpsqv temfnqgraf atvrlpfcgh knicslatiq kiprllvgaa dgylymynld
      361 pqeggecalm kqhrldgsle ttneildsas hdcplvtqty gaaagkaytd dlgavggacl
      421 edeasalrld edsehppmil rtd

 Conserved Domains (3) summary

COG2319
Location:37 → 290

WD40; WD40 repeat [General function prediction only]

sd00039
Location:161 → 200

7WD40; WD40 repeat [structural motif]

cl02567
Location:184 → 363

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from .

Related articles in PubMed

1. mTORC1-Regulated and HUWE1-Mediated WIPI2 Degradation Controls Autophagy Flux. Wan W, et al. Mol Cell, 2018 Oct 18. PMID 30340022
2. Recruitment of TBK1 to cytosol-invading Salmonella induces WIPI2-dependent antibacterial autophagy. Thurston TL, et al. EMBO J, 2016 Aug 15. PMID 27370208, Free PMC Article
3. Fluorescence-based imaging of autophagy progression by human WIPI protein detection. Thost AK, et al. Methods, 2015 Mar. PMID 25462558
4. WIPI β-propellers at the crossroads of autophagosome and lipid droplet dynamics. Pfisterer SG, et al. Biochem Soc Trans, 2014 Oct. PMID 25233424
5. WIPI2b and Atg16L1: setting the stage for autophagosome formation. Wilson MI, et al. Biochem Soc Trans, 2014 Oct. PMID 25233411

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GeneRIFs: Gene References Into Functions

1. Regulation of the intracellular WIPI2 protein level by mTORC1 and HUWE1 is a key determinant of autophagy flux.
2. Results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5-16L1 complex to Wipi2-positive phagophores.
3. Data suggest that, in patients with diabetic kidney disease, urinary excretion of mRNAs for MAP1LC3A, WIPI2, and RB1CC1 is down-regulated as compared to healthy control subjects; these transcripts may serve as urinary autophagy biomarkers. (MAP1LC3A = microtubule associated protein 1 light chain 3; WIPI2 = WD repeat domain phosphoinositide-interacting protein 2; RB1CC1 = RB1 inducible coiled-coil 1)
4. Here the authors show that recruitment of WIPI2, itself essential for anti-bacterial autophagy, is dependent on the localization of catalytically active TBK1 to the vicinity of cytosolic bacteria.
5. The specific autophagosomal localization of both WIPI1 and WIPI2 (refered to as WIPI puncta) has been employed to assess autophagy using fluorescence microscopy methods, such as confocal and live-cell video microscopy
6. Data suggest WIPI1/WIPI2 co-localize with microtubule-associated light chain 3 and autophagy related proteins 2/14L, participate in biogenesis of phagosomes, autophagy, and mobilization of lipids to/from intracellular droplets. [review-like article]
7. WIPI-1 and WIPI-2 are functionally required in mediating the PI3P signal at the onset of autophagy in NB4 cells.
8. Data suggest that WIPI2b directly interacts with dimer of ATG16L1 (autophagy related 16-like 1) and this interaction is linked to production of phosphatidylinositol 3-phosphate in endoplasmic reticulum triggered by autophagosome formation. [REVIEW]
9. WIPI2b binds the membrane surrounding Salmonella and recruits the Atg12-5-16L1 complex, initiating LC3 conjugation, autophagosomal membrane formation, and engulfment of Salmonella.
10. A role for WIPI2 in the progression of omegasomes into autophagosomes, is reported.

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WIPI1 (17q24.2) , ATG18, ATG18A, WPI49 tarjoaa beeta-propellialustaa proteiini-interaktioille.

https://www.ncbi.nlm.nih.gov/gene/55062

Official Symbol

WIPI1provided by HGNC

Official Full Name

WD repeat domain, phosphoinositide interacting 1provided by HGNC

Also known as

ATG18; ATG18A; WIPI49

Summary

This gene encodes a WD40 repeat protein. Members of the WD40 repeat family are key components of many essential biologic functions. They regulate the assembly of multiprotein complexes by presenting a beta-propeller platform for simultaneous and reversible protein-protein interactions. Members of the WIPI subfamily of WD40 repeat proteins have a 7-bladed propeller structure and contain a conserved motif for interaction with phospholipids. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

Expression Ubiquitous expression in placenta (RPKM 11.9), heart (RPKM 11.3) and 25 other tissues See moreOrthologs mouse all

 

Preferred Names

WD repeat domain phosphoinositide-interacting protein 1

Names

WIPI-1 alpha

atg18 protein homolog

 

           ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..364
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="17"
                     /map="17q24.2"
     Protein         1..364
                     /product="WD repeat domain phosphoinositide-interacting
                     protein 1 isoform b"
                     /note="WD repeat domain phosphoinositide-interacting
                     protein 1; WIPI-1 alpha; atg18 protein homolog"
                     /calculated_mol_wt=39811
     Region          <6 ..180="" class="feature" feature_np_001307701.1_region_0="" note="WD40 domain,</span><span id=" region_name="WD40"> found in a number of eukaryotic proteins that cover a
 wide variety of functions including adaptor/regulatory modules in 
signal transduction, pre-mRNA processing and cytoskeleton assembly; 
typically contains a GH dipeptide 11-24 residues from its N-terminus and
 the WD dipeptide at its C-terminus and is 40 residues long, hence the 
name WD40; between GH and WD lies a conserved core; serves as a stable 
propeller-like platform to which proteins can bind either stably or 
reversibly; forms a propeller-like structure with several blades where 
each blade is composed of a four-stranded anti-parallel b-sheet; 
instances with few detectable copies are hypothesized to form larger 
structures by dimerization; each WD40 sequence repeat forms the first 
three strands of one blade and the last strand in the next blade; the 
last C-terminal WD40 repeat completes the blade structure of the first 
WD40 repeat to create the closed ring propeller-structure; residues on 
the top and bottom surface of the propeller are proposed to coordinate 
interactions with other proteins and/or small ligands; 7 copies of the 
repeat are present in this alignment.; cl25539"
                     /db_xref="CDD:330360"

      Region          63..102
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          107..144
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          154..186
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          192..230
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          238..276
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     CDS             1..364
                     /gene="WIPI1"
                     /gene_synonym="ATG18; ATG18A; WIPI49"
                     /coded_by="NM_001320772.1:267..1361"
                     /note="isoform b is encoded by transcript variant 2"
                     /db_xref="CCDS:CCDS82193.1"
                     /db_xref="GeneID:55062"
                     /db_xref="HGNC:HGNC:25471"
                     /db_xref="MIM:609224"
ORIGIN      
        1 mnvyhfkkgt eicnysyssn ilsirlnrqr llvcleesiy ihnikdmkll ktlldipanp
       61 tglcalsinh snsylaypgs ltsgeivlyd gnslktvcti aahegtlaai tfnasgskla
      121 sasekgtvir vfsvpdgqkl yefrrgmkry vtisslvfsm dsqflcassn tetvhifkle
      181 qvtnsrpeep stwsgymgkm fmaatnylpt qvsdmmhqdr afatarlnfs gqrnictlst
      241 iqklprllva sssghlymyn ldpqdggecv likthsllgs gtteenkend lrpslpqsya
      301 atvarpsass astvpgysed ggalrgevip ehefatgpvc lddenefppi ilcrgnqkgk
      361 tkqs
//

Conserved Domains (2) summary

sd00039
Location:63 → 102

7WD40; WD40 repeat [structural motif]

cl25539
Location:6 → 180

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from .

Related articles in PubMed

1. Detection of WIPI1 mRNA as an indicator of autophagosome formation. Tsuyuki S, et al. Autophagy, 2014 Mar. PMID 24384561, Free PMC Article
2. Fluorescence-based imaging of autophagy progression by human WIPI protein detection. Thost AK, et al. Methods, 2015 Mar. PMID 25462558
3. WIPI β-propellers at the crossroads of autophagosome and lipid droplet dynamics. Pfisterer SG, et al. Biochem Soc Trans, 2014 Oct. PMID 25233424
4. WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells. Brigger D, et al. Cell Death Dis, 2014 Jul 3. PMID 24991767, Free PMC ArticleAbstract
   Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the PI3P-dependent autophagic activity during neutrophil differentiation, and that PU.1-dependent WIPI-1 expression is significantly repressed in primary AML patient samples and that the induction of autophagic flux is associated with neutrophil differentiation of APL cells.
5. Freeze-fracture replica immunolabelling reveals human WIPI-1 and WIPI-2 as membrane proteins of autophagosomes. Proikas-Cezanne T, et al. J Cell Mol Med, 2011 Sep. PMID 21564513, Free PMC Article

See all (22) citations in PubMed

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. BAG1, CHMP2B, PEX3, and WIPI1 confirmed a strong differential gene expression, in 355 melanoma samples.
2. The specific autophagosomal localization of both WIPI1 and WIPI2 (refered to as WIPI puncta) has been employed to assess autophagy using fluorescence microscopy methods, such as confocal and live-cell video microscopy
3. Data suggest WIPI1/WIPI2 co-localize with microtubule-associated light chain 3 and autophagy related proteins 2/14L, participate in biogenesis of phagosomes, autophagy, and mobilization of lipids to/from intracellular droplets. [review-like article]
4. WIPI-1 and WIPI-2 are functionally required in mediating the PI3P signal at the onset of autophagy in NB4 cells.
5. the detection of WIPI1 mRNA is likely to be a convenient method of monitoring autophagosome formation in a wide range of cell types
6. Freeze-fracture replica immunolabelling reveals WD-repeat protein interacting with phosphoinositides 1 and 2 (WIPI-1 and WIPI-2) as membrane components of autophagosomes and the plasma membrane (PM).The notion that autophagosomal membranes are profoundly enriched in phosphatidylinositol 3‐phosphate (PtdIns(3)P) [8] is of key interest because autophagy is positively regulated by the activation of the phosphatidylinositol 3‐kinase class III complex 1, also including the tumour suppressor protein Beclin 1, that generates PtdIns(3)P [9]. Previously, we identified the human WIPI gene family that is aberrantly expressed in a variety of human cancer types [10]. We found that the WIPI protein family represents an ancient PtdIns(3)P/PtdIns(3,5)P₂‐binding β‐propeller protein family that includes WIPI‐1 and WIPI‐2 [10], both of which evolved from the yeast ancestral autophagy protein Atg18 [10, 11]. We characterized WIPI‐1 as a PtdIns(3)P‐effector protein functioning in the process of autophagy in human cancer cells [10, 12, 13]. Upon the induction of autophagy and the generation of PtdIns(3)P, both WIPI‐1 and WIPI‐2 specifically bind PtdIns(3)P and localize at initial autophagosomal membranes (phagophore) that are positive for further autophagy proteins, such as microtubule‐associated protein 1 light chain 3 (LC3) and Atg16 [10-14]. To clarify the precise localization of WIPI‐1 and WIPI‐2 upon the induction of autophagy we conducted freeze‐fracture immuno‐electron microscopy (immuno‐EM) because this method allows the employment of native, unfixed cells and, depending on the fracture, either of the two monolayers of a bilayer membrane is preserved [15].
   
7. Studies define a distinct role for WIPI1 and TORC1 signaling in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy.
8. Observational study and genome-wide association study of gene-disease association. (HuGE Navigator)
9. Quantification of WIPI-1 puncta should be suitable to assay mammalian autophagy
10. share an evolutionary conserved function in autophagy and that autophagic capacity may be compromised in human cancers

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