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måndag 25 februari 2019
Tulevaisuuden lääketieteestä uusia non-nukleotidi-STING-agonisteja ONKOIMMUNOTERAPIASSA
https://www.future-science.com/doi/10.4155/fmc-2018-0367?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Future_Medicinal_Chemistry__TrendMD_1&
söndag 24 februari 2019
PI(4)P-5-kinaasi tuottaa PI(4,5)P2 lipidiä antiangiogeenisessa signalointitiessä
http://www.jbc.org/content/286/39/34335.short?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Journal_of_Biological_Chemistry_TrendMD_0
Reviews Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein*
Atsuko Sakurai‡,1, Xiaoying Jian§, Charity J. Lee‡, Yosif Manavski¶, Emmanouil Chavakis¶‖,2, Julie Donaldson**, Paul A. Randazzo§ and J. Silvio Gutkind‡,3 From the ‡Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, ¶Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany, ‖III. Department of Internal Medicine, Cardiology, Goethe University Frankfurt, Germany, and the **Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892 ↵3 To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Dr., Rm. 211, Bethesda, MD 20892. Tel.: 301-496-3695; Fax: 301-402-0823; E-mail: sg39v{at}nih.gov.
Abstract The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells.
Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADP-ribosylation factor 6), which regulates intracellular trafficking of β1 integrin.
However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells.
We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrin-mediated focal adhesions and endothelial cell collapse.
Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix (ECM) and migration.
3-luokan semaforiinit
http://www.jbc.org/content/289/26/17971.long?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Journal_of_Biological_Chemistry_TrendMD_0
Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein*
Reviews Phosphatidylinositol-4-phosphate 5-Kinase and GEP100/Brag2 Protein Mediate Antiangiogenic Signaling by Semaphorin 3E-Plexin-D1 through Arf6 Protein*
Atsuko Sakurai‡,1, Xiaoying Jian§, Charity J. Lee‡, Yosif Manavski¶, Emmanouil Chavakis¶‖,2, Julie Donaldson**, Paul A. Randazzo§ and J. Silvio Gutkind‡,3 From the ‡Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, ¶Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Frankfurt, Germany, ‖III. Department of Internal Medicine, Cardiology, Goethe University Frankfurt, Germany, and the **Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892 ↵3 To whom correspondence should be addressed: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Dr., Rm. 211, Bethesda, MD 20892. Tel.: 301-496-3695; Fax: 301-402-0823; E-mail: sg39v{at}nih.gov.
Abstract The semaphorins are a family of secreted or membrane-bound proteins that are known to guide axons in the developing nervous system. Genetic evidence revealed that a class III semaphorin, semaphorin 3E (Sema3E), and its receptor Plexin-D1 also control the vascular patterning during development. At the molecular level, we have recently shown that Sema3E acts on Plexin-D1 expressed in endothelial cells, thus initiating a novel antiangiogenic signaling pathway that results in the retraction of filopodia in endothelial tip cells.
Sema3E induces the rapid disassembly of integrin-mediated adhesive structures, thereby inhibiting endothelial cell adhesion to the extracellular matrix. This process requires the activation of small GTPase Arf6 (ADP-ribosylation factor 6), which regulates intracellular trafficking of β1 integrin.
However, the molecular mechanisms by which Sema3E-Plexin-D1 activates Arf6 remained to be identified. Here we show that GEP100 (guanine nucleotide exchange protein 100)/Brag2, a guanine nucleotide exchange factor for Arf6, mediates Sema3E-induced Arf6 activation in endothelial cells.
We provide evidence that upon activation by Sema3E, Plexin-D1 recruits phosphatidylinositol-4-phosphate 5-kinase, and its enzymatic lipid product, phosphatidylinositol 4,5-bisphosphate, binds to the pleckstrin homology domain of GEP100. Phosphatidylinositol 4,5-bisphosphate binding to GEP100 enhances its guanine nucleotide exchange factor activity toward Arf6, thus resulting in the disassembly of integrin-mediated focal adhesions and endothelial cell collapse.
Our present study reveals a novel phospholipid-regulated antiangiogenic signaling pathway whereby Sema3E activates Arf6 through Plexin-D1 and consequently controls integrin-mediated endothelial cell attachment to the extracellular matrix (ECM) and migration.
3-luokan semaforiinit
http://www.jbc.org/content/289/26/17971.long?utm_source=TrendMD&utm_medium=cpc&utm_campaign=Journal_of_Biological_Chemistry_TrendMD_0
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