PGFRA_HUMAN » Platelet-derived growth factor receptor alpha

PGFRA_HUMAN » Platelet-derived growth factor receptor alpha
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
PGFRA_HUMAN » Platelet-derived growth factor receptor alpha » PDGF-R-alpha; PDGFR-alpha; Alpha platelet-derived growth factor receptor;Alpha-type platelet-derived growth factor receptor;CD140 antigen-like family member A;CD140a antigen;Platelet-derived growth factor alpha receptor;Platelet-derived growth factor rece
Hydrophobic Thickness 35.6 ± 1.2 Å
Tilt Angle 0 ± 0°
ΔGtransfer -52.0 kcal/mol
ΔGfold -30.3 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 525-550 (522-552)
Pathways

Calcium signaling pathway (KEGG)

Cytokine-cytokine receptor interaction (KEGG)

Endocytosis (KEGG)

Focal adhesion (KEGG)

Gap junction (KEGG)

Glioma (KEGG)

HTLV-I infection (KEGG)

Immune System (Reactome)

MAPK signaling pathway (KEGG)

Melanoma (KEGG)

Pathways in cancer (KEGG)

PI3K-Akt signaling pathway (KEGG)

Prostate cancer (KEGG)

Regulation of actin cytoskeleton (KEGG)

Signal Transduction (Reactome)

PDB 1gq5 (11-94)
OPM none
Complexes none
Interactions

EGFR, Complex: EGFR:PGFRA, PubMed

ITAV, Complex: PGFRA:ITAV, PubMed

ITB3, Complex: ITB3:PGFRA, PubMed

KASH5, Complex: PGFRA:KASH5

KIT, Complex: PGFRA:KIT, PubMed

PGFRB, Complex: NHRF1:PGFRA:PGFRB, PDBID: 1gq5

TGFR2, Complex: PGFRA:TGFR2, PubMed

Domains

AA: 216-307, PDBID: 4KC3, Subunit B, Seq Identity:31%, Immunoglobulin I-set domain

AA: 319-411, PDBID: 2CPC, Subunit A, Seq Identity:30%, Immunoglobulin I-set domain

AA: 593-950, PDBID: 1AYC, Subunit P, Seq Identity:85%, Protein tyrosine kinase

UniProt annotation for PGFRA_HUMAN » Platelet-derived growth factor receptor alpha
FUNCTION: 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.

CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

ENZYME REGULATION: Present in an inactive conformation in the absence of bound ligand. Binding of PDGFA and/or PDGFB leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by imatinib, nilotinib and sorafenib.

SUBUNIT: Interacts with homodimeric PDGFA, PDGFB and PDGFC, and with heterodimers formed by PDGFA and PDGFB. Monomer in the absence of bound ligand. Interaction with dimeric PDGFA, PDGFB and/or PDGFC leads to receptor dimerization, where both PDGFRA homodimers and heterodimers with PDGFRB are observed. Interacts (tyrosine phosphorylated) with SHB (via SH2 domain) (By similarity). Interacts (tyrosine phosphorylated) with SHF (via SH2 domain). Interacts (tyrosine phosphorylated) with SRC (via SH2 domain). Interacts (tyrosine phosphorylated) with PIK3R1. Interacts (tyrosine phosphorylated) with PLCG1 (via SH2 domain). Interacts (tyrosine phosphorylated) with CRK, GRB2 and GRB7. Interacts with human cytomegalovirus/HHV-5 envelop glycoprotein B/gB.

TISSUE SPECIFICITY: Detected in platelets (at protein level). Widely expressed. Detected in brain, fibroblasts, smooth muscle, heart, and embryo. Expressed in primary and metastatic colon tumors and in normal colon tissue.

DISEASE: Note=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.

DISEASE: Gastrointestinal stromal tumor (GIST) OMIM: Common mesenchymal neoplasms arising in the gastrointestinal tract, most often in the stomach. They are histologically, immunohistochemically, and genetically different from typical leiomyomas, leiomyosarcomas, and schwannomas. Most GISTs are composed of a fairly uniform population of spindle-shaped cells. Some tumors are dominated by epithelioid cells or contain a mixture of spindle and epithelioid morphologies. Primary GISTs in the gastrointestinal tract commonly metastasize in the omentum and mesenteries, often as multiple nodules. However, primary tumors may also occur outside of the gastrointestinal tract, in other intra-abdominal locations, especially in the omentum and mesentery. entry may be involved in disease pathogenesis. Mutations causing PDGFRA constitutive activation have been found in gastrointestinal stromal tumors lacking KIT mutations (PubMed).

UniProt features for PGFRA_HUMAN » Platelet-derived growth factor receptor alpha
SIGNAL 1 23
CHAIN 24 1089 Platelet-derived growth factor receptor alpha.
DOMAIN 24 113 Ig-like C2-type 1.
DOMAIN 117 201 Ig-like C2-type 2.
DOMAIN 202 306 Ig-like C2-type 3.
DOMAIN 319 410 Ig-like C2-type 4.
DOMAIN 414 517 Ig-like C2-type 5.
DOMAIN 593 954 Protein kinase.
ACT_SITE 818 818 Proton acceptor (By similarity).
SITE 578 579 Breakpoint for interstitial deletion to form the FIP1L1-PDGFRA fusion protein.
DISULFID 49 100 By similarity.
DISULFID 150 189 By similarity.
DISULFID 235 290 By similarity.
DISULFID 435 501 By similarity.
Amino Acid Sequence for PGFRA_HUMAN » Platelet-derived growth factor receptor alpha
MGTSHPAFLV LGCLLTGLSL ILCQLSLPSI LPNENEKVVQ LNSSFSLRCF GESEVSWQYP MSEEESSDVE IRNEENNSGL FVTVLEVSSA SAAHTGLYTC YYNHTQTEEN ELEGRHIYIY VPDPDVAFVP LGMTDYLVIV EDDDSAIIPC RTTDPETPVT LHNSEGVVPA SYDSRQGFNG TFTVGPYICE ATVKGKKFQT IPFNVYALKA TSELDLEMEA LKTVYKSGET IVVTCAVFNN EVVDLQWTYP GEVKGKGITM LEEIKVPSIK LVYTLTVPEA TVKDSGDYEC AARQATREVK EMKKVTISVH EKGFIEIKPT FSQLEAVNLH EVKHFVVEVR AYPPPRISWL KNNLTLIENL TEITTDVEKI QEIRYRSKLK LIRAKEEDSG HYTIVAQNED AVKSYTFELL TQVPSSILDL VDDHHGSTGG QTVRCTAEGT PLPDIEWMIC KDIKKCNNET SWTILANNVS NIITEIHSRD RSTVEGRVTF AKVEETIAVR CLAKNLLGAE NRELKLVAPT LRSELTVAAA VLVLLVIVII SLIVLVVIWK QKPRYEIRWR VIESISPDGH EYIYVDPMQL PYDSRWEFPR DGLVLGRVLG SGAFGKVVEG TAYGLSRSQP VMKVAVKMLK PTARSSEKQA LMSELKIMTH LGPHLNIVNL LGACTKSGPI YIITEYCFYG DLVNYLHKNR DSFLSHHPEK PKKELDIFGL NPADESTRSY VILSFENNGD YMDMKQADTT QYVPMLERKE VSKYSDIQRS LYDRPASYKK KSMLDSEVKN LLSDDNSEGL TLLDLLSFTY QVARGMEFLA SKNCVHRDLA ARNVLLAQGK IVKICDFGLA RDIMHDSNYV SKGSTFLPVK WMAPESIFDN LYTTLSDVWS YGILLWEIFS LGGTPYPGMM VDSTFYNKIK SGYRMAKPDH ATSEVYEIMV KCWNSEPEKR PSFYHLSEIV ENLLPGQYKK SYEKIHLDFL KSDHPAVARM RVDSDNAYIG VTYKNEEDKL KDWEGGLDEQ RLSADSGYII PLPDIDPVPE EEDLGKRNRH SSQTSEESAI ETGSSSSTFI KREDETIEDI DMMDDIGIDS SDLVEDSFL