SHEARS SB. Inositolipyrofosfaatit; (InsPP) Miksi niin monta fosfaattia inositolijärjestelmällä?

https://www.ncbi.nlm.nih.gov/pubmed/25453220

Adv Biol Regul. 2015 Jan;57:203-16. doi: 10.1016/j.jbior.2014.09.015. Epub 2014 Oct 5.

Inositol pyrophosphates: why so many phosphates?

Shears SB¹.

1

Inositol Signaling Group, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, DHHS, PO Box 12233, Research Triangle Park, NC 27709, USA. Electronic address: Shears@niehs.nih.gov.

Abstract

The inositol pyrophosphates (PP-InsPs) are a specialized group of "energetic" signaling molecules found in yeasts, plants and animals. PP-InsPs boast the most crowded three dimensional phosphate arrays found in Nature; multiple phosphates and diphosphates are crammed around the six-carbon, inositol ring. Yet, phosphate esters are also a major energy currency in cells. So the synthesis of PP-InsPs, and the maintenance of their levels in the face of a high rate of ongoing turnover, all requires significant bioenergetic input. What are the particular properties of PP-InsPs that repay this investment of cellular energy? Potential answers to that question are discussed here, against the backdrop of a recent hypothesis that signaling by PP-InsPs is evolutionarily ancient. The latter idea is extended herein, with the proposal that the primordial origins of PP-InsPs is reflected in the apparent lack of isomeric specificity of certain of their actions. Nevertheless, there are other aspects of signaling by these polyphosphates that are more selective for a particular PP-InsP isomer. Consideration of the nature of both specific and non-specific effects of PP-InsPs can help rationalize why such molecules possess so many phosphates.

Published by Elsevier Ltd.

KEYWORDS:

Analogs; Cell-signaling; Diphosphoinositol polyphosphates; Inositol pyrophosphates; Kinase; Phosphorylation; Structure

PMID:

25453220

PMCID:

PMC4291286

DOI:

10.1016/j.jbior.2014.09.015

[Indexed for MEDLINE]

Free PMC Article

KOSKA ON INOSITOLIPYROFOSFAATTEJA, on myös INOSITOLIPYROFOSFATAASEJA:

IP6K2 (3p21.31) ( inositolihexakisfosfaattikinaasi 2) ja PP-InsPx , Inositolipyrofosfaatit. apoptoositekijäin säätelijänä

 IP6K2 (inositolhexakisphosphatekinase 2), PiUS

Also known as  PIUS (Pi uptake stimulator); IHPK2; InsP6K2

Summary: This gene encodes a protein that belongs to the inositol phosphokinase (IPK) family. This protein is likely responsible for the conversion of inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5).

 It may also convert 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4 and affect the growth suppressive and apoptotic activities of interferon-beta in some ovarian cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Expression Ubiquitous expression in bone marrow (RPKM 16.6), skin (RPKM 16.3) and 25 other tissues See more Orthologs mouse all

Preferred Names

inositol hexakisphosphate kinase 2

Names

ATP:1D-myo-inositol-hexakisphosphate phosphotransferase

inositol hexaphosphate kinase 2

insp6 kinase 2

pi uptake stimulator

 Protein   (426 a.a) NP_001005909.1  inositol hexakisphosphate kinase 2 isoform a

ORIGIN      
        1 mspaframdv eprakgvlle pfvhqvgghs cvlrfnettl ckplvprehq fyetlpaemr
       61 kftpqykgvv svrfeededr nlcliayplk gdhgivdivd nsdcepkskl lrwttnkkhh
      121 vletektpkd wvrqhrkeek mkshkleeef ewlkksevly ytvekkgnis sqlkhynpws
      181 mkchqqqlqr mkenakhrnq ykfillenlt sryevpcvld lkmgtrqhgd daseekaanq
      241 irkcqqstsa vigvrvcgmq vyqagsgqlm fmnkyhgrkl svqgfkealf qffhngrylr
      301 rellgpvlkk ltelkavler qesyrfysss llviydgker pevvldsdae dledlseesa
      361 desagayayk pigassvdvr midfahttcr lygedtvvhe gqdagyifgl qslidivtei
      421 seesge

Conserved Domains (1) summary

pfam03770
Location:203 → 418

IPK; Inositol polyphosphate kinase

Inositol polyphosphate kinase

ArgRIII has has been demonstrated to be an inositol polyphosphate kinase.  (https://ec.asm.org/content/7/3/471)

1. Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2. Chakraborty A, et al. Proc Natl Acad Sci U S A, 2011 Feb 8. PMID 21262846, Free PMC Article
2. Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. Nagata E, et al. J Biol Chem, 2005 Jan 14. PMID 15533939 
3. Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics. Morrison BH, et al. Oncogene, 2002 Mar 14. PMID 11896621, Free PMC Article
4.  Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis. Gu C, et al. J Med Chem, 2019 Feb 14. PMID 30624931, Free PMC Article  https://www.ncbi.nlm.nih.gov/pubmed/30624931/ 
5. IP6K structure and the molecular determinants of catalytic specificity in an inositol phosphate kinase family. Wang H, et al. Nat Commun, 2014 Jun 24. PMID 24956979, Free PMC Article
   

See all (36) citations in PubMed

GeneRIFs: Gene References Into Functions

1. An alpha-helical pair and a rare, two-turn 310 helix, that together form a substrate-binding pocket of IP6K2.
2. FGF2-signaling involves the inositol polyphosphate cascade, including inositol hexakisphosphate kinase (IP6K), and demonstrate that IP6K1,2 regulates Runx2 and osteoblast gene expression.
3. Genetic polymorphisms in IP6K2 gene is associated with autoimmune disease.
4. Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2.
5. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets
6. InsP6K2 is a physiologic mediator of cell death
7. IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappaB-mediated signaling and is partially responsible for the apoptotic activity of IHPK2.
8. IHPK2 over expression enhances sensitivity of ovarian carcinoma cells to radiation, IFN-beta, caspase 8 and DR4

 

 

On mahdollista, että inositoli 5-pyrofosfaatti (PP-IP5) voi estää DNA korjaantumisen ja siten edistää apoptoosia syövän hoidossa herkistämällä syöpäsoluja.

It is possible that InsP5PP, which contains a pyrophosphate linkage, may function as an ... InsP5PP may inhibit DNA repair and thereby promote apoptosis.

INOSITOLI hexacisfosfaattikinaasi 2 (IP62K) säätelee stimuloivasti IFN-beeta ja gammasäteilyn apoptoottista vaikutusta kaspaasi-8 tietä.

LÄHDE : Bei H Morrison,¹ Joseph A Bauer et al. Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics
Oncogene. 2002 March 14; 21(12): 1882–1889. Oncogene. Author manuscript; available in PMC 2007 October 29. USA.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2043497

Tutkijat ovat identifioineet inositolihexacisfosfaattikinaasi-2:n ( IP6K2) mahdollisena apoptoosin säätelijänä.
Jos tätä entsyymiä IP6K2 ilmenee ylimäärin, lisääntyy apoptoosi, jota indusoi interferoni beeta (IFN-beeta) ja sytotoksiset agenssit ( tutkittuna ovariaalikarsinoomasoluissa).
IP6K2 tekee inositolipolyfosfaateista IP6 ja IP5 vastaavia pyrofosfaatteja.

IP6K2_HUMAN, Q9UHH9
Tämän entsyymin funktio on muuttaa IP6 muotoon ”IP7”, joka kuitenkin pitää ilmaista eri tavalla, koska inositolissa on vain 6 kohtaa, johon lisäliitos voidaan tehdä. Viidessä on yksi ja yhdessä on kaksi fosfaattia: PP-IP5 on tulos, diphosphoinositol pentakisphosphate(InsP7/PP-InsP5).
Mutta sama entsyymi voi muuttaa myös IP5 molekyylin muotoon PP-IP4, lisäämällä fosfaatin 2- asemaan inositolirengasta. (1,3,4,5,6-pentakisphosphate (InsP5) muotoon PP-InsP4)
Entsyymin muita nimiä:
ATP:1D-myo-inositol-hexakisphosphate phosphotransferase
InsP6 kinase 2
2, 3P(i)-uptake stimulator
3Pi uptake stimulator
2, inositol hexakisphosphate kinase 2
1, 2 inositol hexaphosphate kinase 2 1,

GEENI koodaa proteiinia, joka kuuluu IPK-perheeseen ( inositolifosfokinaasien perheesen) ja tekee yllä olevat muutokset IP6 ja tiettyyn IP5 molekyyliin. Se voi vaikuttaa stimuloimalla IFN-beetan kasvua suppressoivia ja apoptoottisia ominaisuuksia( Tämä on havaittu ovariaalisyövästä) Alternatiivinen pilkkoutuminen geenistä johtaa multippeleihin transkripteihin, jotka koodaavat eri isoformeja.

http://www.genecards.org/cgi-bin/carddisp.pl?gene=IP6K2

ESIMERKKI:
Tässä allaolevassa tutkimuksessa vertailtiin sekä IFN-beeta vaikutusta että gamma- säteilytystä ovariaalisyöpäsolukuoleman (apoptoosin) indusoijina ja tutkijat osoittivat että IP6K2 expressio herkisti tuumorisolut näille kummallekin vaikutukselle.
Jos säteilyttämättömiin syöpäsoluihin transfektoitiin IP6K2, muodostui vähemmän syöpäkolonioita kuin säteilyttämättömiin pelkkää vektoria ilmentäviin syöpäsoluihin
IP6K2 yliexpressoituminen aiheutti lisääntyvää radiosensitiivisyyttä ja se ilmeni alentuneena syöpäkolonioitten muodostumisena. ( CFU= colony forming units)
Sekä IFN-beeta että säteilyttäminen indusoivat kaspaasi-8 tekijää.
http://www.researchapoptosis.com/apoptosis/images/chart-ie.gif
IFN-beeta ( mutta ei gammasäteily), indusoi syöpäsoluissa TRAIL.
Gammasäteily, mutta ei IFN beeta, indusoi DR4mRNA.
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A8980&rendertype=figure&id=A8987
Ne apoptoottiset vaikutukset , mitkä tulivat IFN-beetasta ja gammasäteilystä, blokeerautuivat kun expressoitui dominantti negatiivinen mutantti DR5A reseptoria ( death receptoria 5) tai Bcl-2:ta. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=eurekah&part=A8980&rendertype=figure&id=A8987
Kaspaasi -8 mRNA:n indusoituminen oli paljon selvempää niissä soluissa joissa ilmeni IP6K2 verrattuna pelkkää vektoria ilmentäviin soluihin.

http://www.bioscience.org/2007/v12/af/2281/fig1.jp
 DISCUSSION:
In ovarian carcinoma cell lines, IFN-β and γ-irradiation induce apoptosis using similar but not identical pathways. In sensitive cells, IFN-β upregulates TRAIL, and to a lesser extent, caspase 8 (Figure 5a). IFN-β-induced apoptosis has been associated with TRAIL induction in several different tumor cell lines (Chawla-Sarkar et al., 2001; Zhang et al., 1999). γ-irradiation clearly upregulates caspase 8 and DR4 mRNA (Figure 5b) as well as caspase 8 activity (Figure 6a). This is consistent with our previous study showing induction of apoptosis following ionizing radiation (Gong and Almasan, 2000). Transcriptional induction of DR4 following radiation has also been reported in lung carcinoma cell lines (Guan et al., 2001). Our studies are consistent with others, who have described caspase 8 activation following radiation of Jurkat cells (Belka et al., 2000). In three different ovarian carcinoma cell lines, we observed no induction of TRAIL following radiation treatment. This is in contrast to hematologic cells in which both TRAIL and Fas upregulation has been described (Gong and Almasan, 2000). Combination therapy utilizing TRAIL and cytotoxic agents (cisplatin, doxorubicin, or paclitaxel) has been proposed, in an effort to overcome the chemoresistance that usually develops following treatment of women with ovarian carcinoma (Cuello et al., 2001). The p53 status of ovarian carcinoma cells did not correlate with sensitivity to death inducers. In fact, cell lines with mutant p53 (NIH-OVCAR-3, Caov-3) were more sensitive to IFN-β and γ-irradiation than cells containing wild-type p53 (Hey).
We found that DR5Δ protects against apoptosis initiated by both IFN-β and γ-irradiation, confirming that TRAIL : DR-mediated signaling occurs following treatment with both death inducers. Thus, downstream effects of TRAIL and one of its receptors can be blocked by DR5Δ. Combination treatment with both modalities resulted in additive, rather than synergistic antiproliferative effects (Figure 4b). Such additivity is consistent with upregulation of the ligand TRAIL and its receptor DR4, components of the same apoptotic pathway. DR4 and DR5, both agonistic receptors for TRAIL, form homomeric and heteromeric complexes upon ligand binding (Kischkel et al., 2000). Recent reports indicate that ligation of DR4 (Sprick et al., 2000) and DR5 (Bodmer et al., 2000) lead to caspase 8 activation, using a signaling paradigm that is similar, but not identical, to those induced by TNF-α and FasL. Caspase 8 is activated as part of the death-inducing signaling complex (DISC). We show that caspase 8 activity was induced more strongly by radiation compared to IFN-β (Figure 6a,b). Yet caspase 8 activity following combination treatment with IFN-β and γ-irradiation was no greater than that following radiation alone (not shown). It is possible that in NIH-OVCAR-3 cells, caspase 8 activity is already maximized following radiation.
Overexpression of IP6K2 enhanced the degree of apoptosis induced by several different stimuli, including chemotherapeutic drugs, IFNs, and γ-irradiation. Expression of the dominant negative SUB mutant interferes with kinase activity (Morrison et al., 2001) and abrogates death induced by all these agents. IP6K2 protein levels are elevated following IFN-β and irradiation (Figure 1). These findings suggest that IP6K2 functions as a positive regulator of cell death pathways. The mechanism by which this inositol phosphate kinase promotes apoptosis is unclear. IP6K2 converts IP₆ to InsP₅PP. It is possible that InsP₅PP, which contains a pyrophosphate linkage, may function as an energy source that facilitates DISC assembly or signal transduction to the caspase cascade. Proteins that bind IP₆ include the clathrin assembly proteins AP-2, AP-3, and AP-180 (involved in membrane fusion) (Norris et al., 1995; Voglmaier et al., 1992; Ye et al., 1995), the synaptotagmins (involved in exocytosis of synaptic vesicles) (Mehrotra et al., 2000) and arrestin (which acts as an adapter during endocytosis) (Gaidarov et al., 1999). All these proteins are closely associated with the plasma membrane. Studies in yeast have suggested that the higher inositol phosphates play a role in mRNA export from the nucleus (Saiardi et al., 2000; York et al., 1999). Finally, IP₆ was found to specifically stimulate repair of double-strand breaks in DNA by the process of nonhomologous end-joining in vitro (Hanakahi et al., 2000). If the functions of InsP₅PP and IP₆ prove to be antagonistic, InsP₅PP may inhibit DNA repair and thereby promote apoptosis.