6jok

Structural highlights

Disease

PGFRA_HUMAN Myeloid neoplasm associated with PDGFRA rearrangement;Primary hypereosinophilic syndrome;Precursor B-cell acute lymphoblastic leukemia;Gastrointestinal stromal tumor. A chromosomal aberration involving PDGFRA is found in some cases of hypereosinophilic syndrome. Interstitial chromosomal deletion del(4)(q12q12) causes the fusion of FIP1L1 and PDGFRA (FIP1L1-PDGFRA). Mutations that cause overexpression and/or constitutive activation of PDGFRA may be a cause of hypereosinophilic syndrome.^[1] The gene represented in this entry may be involved in disease pathogenesis. Mutations causing PDGFRA constitutive activation have been found in gastrointestinal stromal tumors lacking KIT mutations (PubMed:12522257).^[2]

Function

PGFRA_HUMAN Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for normal skeleton development and cephalic closure during embryonic development. Required for normal development of the mucosa lining the gastrointestinal tract, and for recruitment of mesenchymal cells and normal development of intestinal villi. Plays a role in cell migration and chemotaxis in wound healing. Plays a role in platelet activation, secretion of agonists from platelet granules, and in thrombin-induced platelet aggregation. Binding of its cognate ligands - homodimeric PDGFA, homodimeric PDGFB, heterodimers formed by PDGFA and PDGFB or homodimeric PDGFC -leads to the activation of several signaling cascades; the response depends on the nature of the bound ligand and is modulated by the formation of heterodimers between PDGFRA and PDGFRB. Phosphorylates PIK3R1, PLCG1, and PTPN11. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, mobilization of cytosolic Ca(2+) and the activation of protein kinase C. Phosphorylates PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, and thereby mediates activation of the AKT1 signaling pathway. Mediates activation of HRAS and of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3 and STAT5A and/or STAT5B. Receptor signaling is down-regulated by protein phosphatases that dephosphorylate the receptor and its down-stream effectors, and by rapid internalization of the activated receptor.^{[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]}

References

1. ↑ Griffin JH, Leung J, Bruner RJ, Caligiuri MA, Briesewitz R. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7830-5. Epub 2003 Jun 13. PMID:12808148 doi:http://dx.doi.org/10.1073/pnas.0932698100
2. ↑ Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003 Jan 31;299(5607):708-10. Epub 2003 Jan 9. PMID:12522257 doi:http://dx.doi.org/10.1126/science.1079666
3. ↑ Rosenkranz S, Ikuno Y, Leong FL, Klinghoffer RA, Miyake S, Band H, Kazlauskas A. Src family kinases negatively regulate platelet-derived growth factor alpha receptor-dependent signaling and disease progression. J Biol Chem. 2000 Mar 31;275(13):9620-7. PMID:10734113
4. ↑ Selheim F, Fukami MH, Holmsen H, Vassbotn FS. Platelet-derived-growth-factor-induced signalling in human platelets: phosphoinositide-3-kinase-dependent inhibition of platelet activation. Biochem J. 2000 Sep 1;350 Pt 2:469-75. PMID:10947961
5. ↑ Gilbertson DG, Duff ME, West JW, Kelly JD, Sheppard PO, Hofstrand PD, Gao Z, Shoemaker K, Bukowski TR, Moore M, Feldhaus AL, Humes JM, Palmer TE, Hart CE. Platelet-derived growth factor C (PDGF-C), a novel growth factor that binds to PDGF alpha and beta receptor. J Biol Chem. 2001 Jul 20;276(29):27406-14. Epub 2001 Apr 10. PMID:11297552 doi:10.1074/jbc.M101056200
6. ↑ Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003 Jan 31;299(5607):708-10. Epub 2003 Jan 9. PMID:12522257 doi:http://dx.doi.org/10.1126/science.1079666
7. ↑ Yu JC, Heidaran MA, Pierce JH, Gutkind JS, Lombardi D, Ruggiero M, Aaronson SA. Tyrosine mutations within the alpha platelet-derived growth factor receptor kinase insert domain abrogate receptor-associated phosphatidylinositol-3 kinase activity without affecting mitogenic or chemotactic signal transduction. Mol Cell Biol. 1991 Jul;11(7):3780-5. PMID:1646396
8. ↑ Kelly JD, Haldeman BA, Grant FJ, Murray MJ, Seifert RA, Bowen-Pope DF, Cooper JA, Kazlauskas A. Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J Biol Chem. 1991 May 15;266(14):8987-92. PMID:1709159
9. ↑ Vantler M, Huntgeburth M, Caglayan E, Ten Freyhaus H, Schnabel P, Rosenkranz S. PI3-kinase/Akt-dependent antiapoptotic signaling by the PDGF alpha receptor is negatively regulated by Src family kinases. FEBS Lett. 2006 Dec 22;580(30):6769-76. Epub 2006 Nov 27. PMID:17141222 doi:http://dx.doi.org/10.1016/j.febslet.2006.11.034
10. ↑ von Bubnoff N, Gorantla SP, Engh RA, Oliveira TM, Thone S, Aberg E, Peschel C, Duyster J. The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro. Oncogene. 2011 Feb 24;30(8):933-43. doi: 10.1038/onc.2010.476. Epub 2010 Oct 25. PMID:20972453 doi:http://dx.doi.org/10.1038/onc.2010.476
11. ↑ Elling C, Erben P, Walz C, Frickenhaus M, Schemionek M, Stehling M, Serve H, Cross NC, Hochhaus A, Hofmann WK, Berdel WE, Muller-Tidow C, Reiter A, Koschmieder S. Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease. Blood. 2011 Mar 10;117(10):2935-43. doi: 10.1182/blood-2010-05-286757. Epub 2011 , Jan 11. PMID:21224473 doi:http://dx.doi.org/10.1182/blood-2010-05-286757
12. ↑ Severe N, Miraoui H, Marie PJ. The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011 Jul 8;286(27):24443-50. doi: 10.1074/jbc.M110.197525. Epub 2011, May 19. PMID:21596750 doi:10.1074/jbc.M110.197525
13. ↑ Matsui T, Pierce JH, Fleming TP, Greenberger JS, LaRochelle WJ, Ruggiero M, Aaronson SA. Independent expression of human alpha or beta platelet-derived growth factor receptor cDNAs in a naive hematopoietic cell leads to functional coupling with mitogenic and chemotactic signaling pathways. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8314-8. PMID:2554309
14. ↑ Vassbotn FS, Havnen OK, Heldin CH, Holmsen H. Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor. J Biol Chem. 1994 May 13;269(19):13874-9. PMID:8188664
15. ↑ Osornio-Vargas AR, Lindroos PM, Coin PG, Badgett A, Hernandez-Rodriguez NA, Bonner JC. Maximal PDGF-induced lung fibroblast chemotaxis requires PDGF receptor-alpha. Am J Physiol. 1996 Jul;271(1 Pt 1):L93-9. PMID:8760137
16. ↑ Bazenet CE, Gelderloos JA, Kazlauskas A. Phosphorylation of tyrosine 720 in the platelet-derived growth factor alpha receptor is required for binding of Grb2 and SHP-2 but not for activation of Ras or cell proliferation. Mol Cell Biol. 1996 Dec;16(12):6926-36. PMID:8943348