VGFR1_HUMAN » Vascular endothelial growth factor receptor 1

VGFR1_HUMAN » Vascular endothelial growth factor receptor 1
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Topology in Plasma membrane
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cytoplasmic side
VGFR1_HUMAN » Vascular endothelial growth factor receptor 1 » VEGFR-1; Vascular permeability factor receptor;Tyrosine-protein kinase receptor FLT;Flt-1;Tyrosine-protein kinase FRT;Fms-like tyrosine kinase 1;
Hydrophobic Thickness 36.0 ± 3.8 Å
Tilt Angle 1 ± 0°
ΔGtransfer -35.1 kcal/mol
ΔGfold -20.9 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 759-784 (756-786)
Pathways

Bevacizumab Pathway (SMPDB)

Cytokine-cytokine receptor interaction (KEGG)

Endocytosis (KEGG)

Focal adhesion (KEGG)

HIF-1 signaling pathway (KEGG)

PI3K-Akt signaling pathway (KEGG)

Rheumatoid arthritis (KEGG)

Signal Transduction (Reactome)

Transcriptional misregulation in cancer (KEGG)

Vatalanib Pathway (SMPDB)

PDB 1qsv (129-229), 1qsz (129-229), 3hng (801-1158), 4cl7 (A/B/C/D=132-225), 2xac (C/X=129-226), 1qty (T/U/X/Y=129-229), 1rv6 (X/Y=130-229), 1flt (X/Y=132-226), 4ckv (X=132-225)
OPM none
Complexes

VGFR1:VGFR1_HUMAN

Interactions

LDLR, Complex: VGFR1:LDLR, PubMed

NRP1, Complex: NRP1:VGFR1, PubMed

NRP2, Complex: NRP2:VGFR1, PubMed

PTPRB, Complex: VGFR1:PTPRB, PubMed

PTPRJ, Complex: VGFR1:PTPRJ

ROBO4, Complex: ROBO4:VGFR1, PubMed

VGFR1, Complex: Homodimer of vascular endothelial growth factor receptor 1, PDBID: 4CL7

VGFR2, Complex: VGFR1:VGFR2, PubMed

Domains

AA: 235-326, PDBID: 2X1W, Subunit L, Seq Identity:26%, Immunoglobulin domain

AA: 337-426, PDBID: 2EO1, Subunit A, Seq Identity:30%, Immunoglobulin I-set domain

AA: 560-640, PDBID: 3DMK, Subunit C, Seq Identity:31%, Immunoglobulin domain

AA: 661-748, PDBID: 3KVQ, Subunit A, Seq Identity:37%, Immunoglobulin I-set domain

AA: 827-1154, PDBID: 3HNG, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for VGFR1_HUMAN » Vascular endothelial growth factor receptor 1
FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at "Ser-473". Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at "Tyr-418" by unknown means and promotes tumor cell invasion.

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 VEGFA, VEGFB or PGF leads to dimerization and activation by autophosphorylation on tyrosine residues.

SUBUNIT: Interacts with VEGFA, VEGFB and PGF. Monomer in the absence of bound VEGFA, VEGFB or PGF. Homodimer in the presence of bound VEGFA, VEGFB and PGF. Can also form a heterodimer with KDR. Interacts (when tyrosine phosphorylated) with CBL, CRK, GRB2, NCK1, PIK3R1, PLCG, PSEN1 and PTPN11. Probably interacts also with PTPRB. Interacts with GNB2L1/RACK1. Identified in a complex with CBL and CD2AP.

TISSUE SPECIFICITY: Detected in normal lung, but also in placenta, liver, kidney, heart and brain tissues. Specifically expressed in most of the vascular endothelial cells, and also expressed in peripheral blood monocytes. Isoform 2 is strongly expressed in placenta. Isoform 3 is expressed in corneal epithelial cells (at protein level). Isoform 3 is expressed in vascular smooth muscle cells (VSMC).

INDUCTION: Up-regulated in coculture of VSMC/endothelial cell (EC) or by direct exposure to VEGF of VSMC monoculture. Up-regulated from the second trimester of pregnancy to the term and in the placenta of women with preeclampsia (PE). Up-regulated in monocytes exposed to bacterial lipopolysaccharide (LPS).

DOMAIN: The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFA binding.

DISEASE: Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages.

DISEASE: Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia.

UniProt features for VGFR1_HUMAN » Vascular endothelial growth factor receptor 1
SIGNAL 1 26
CHAIN 27 1338 Vascular endothelial growth factor receptor 1.
DOMAIN 32 123 Ig-like C2-type 1.
DOMAIN 151 214 Ig-like C2-type 2.
DOMAIN 230 327 Ig-like C2-type 3.
DOMAIN 335 421 Ig-like C2-type 4.
DOMAIN 428 553 Ig-like C2-type 5.
DOMAIN 556 654 Ig-like C2-type 6.
DOMAIN 661 747 Ig-like C2-type 7.
DOMAIN 827 1158 Protein kinase.
ACT_SITE 1022 1022 Proton acceptor (By similarity).
SITE 767 768 Cleavage; by PSEN1 (Probable).
DISULFID 53 107 By similarity.
DISULFID 158 207
DISULFID 252 311 By similarity.
DISULFID 454 535 By similarity.
DISULFID 577 636 By similarity.
DISULFID 682 731 By similarity.
Amino Acid Sequence for VGFR1_HUMAN » Vascular endothelial growth factor receptor 1
MVSYWDTGVL LCALLSCLLL TGSSSGSKLK DPELSLKGTQ HIMQAGQTLH LQCRGEAAHK WSLPEMVSKE SERLSITKSA CGRNGKQFCS TLTLNTAQAN HTGFYSCKYL AVPTSKKKET ESAIYIFISD TGRPFVEMYS EIPEIIHMTE GRELVIPCRV TSPNITVTLK KFPLDTLIPD GKRIIWDSRK GFIISNATYK EIGLLTCEAT VNGHLYKTNY LTHRQTNTII DVQISTPRPV KLLRGHTLVL NCTATTPLNT RVQMTWSYPD EKNKRASVRR RIDQSNSHAN IFYSVLTIDK MQNKDKGLYT CRVRSGPSFK SVNTSVHIYD KAFITVKHRK QQVLETVAGK RSYRLSMKVK AFPSPEVVWL KDGLPATEKS ARYLTRGYSL IIKDVTEEDA GNYTILLSIK QSNVFKNLTA TLIVNVKPQI YEKAVSSFPD PALYPLGSRQ ILTCTAYGIP QPTIKWFWHP CNHNHSEARC DFCSNNEESF ILDADSNMGN RIESITQRMA IIEGKNKMAS TLVVADSRIS GIYICIASNK VGTVGRNISF YITDVPNGFH VNLEKMPTEG EDLKLSCTVN KFLYRDVTWI LLRTVNNRTM HYSISKQKMA ITKEHSITLN LTIMNVSLQD SGTYACRARN VYTGEEILQK KEITIRDQEA PYLLRNLSDH TVAISSSTTL DCHANGVPEP QITWFKNNHK IQQEPGIILG PGSSTLFIER VTEEDEGVYH CKATNQKGSV ESSAYLTVQG TSDKSNLELI TLTCTCVAAT LFWLLLTLFI RKMKRSSSEI KTDYLSIIMD PDEVPLDEQC ERLPYDASKW EFARERLKLG KSLGRGAFGK VVQASAFGIK KSPTCRTVAV KMLKEGATAS EYKALMTELK ILTHIGHHLN VVNLLGACTK QGGPLMVIVE YCKYGNLSNY LKSKRDLFFL NKDAALHMEP KKEKMEPGLE QGKKPRLDSV TSSESFASSG FQEDKSLSDV EEEEDSDGFY KEPITMEDLI SYSFQVARGM EFLSSRKCIH RDLAARNILL SENNVVKICD FGLARDIYKN PDYVRKGDTR LPLKWMAPES IFDKIYSTKS DVWSYGVLLW EIFSLGGSPY PGVQMDEDFC SRLREGMRMR APEYSTPEIY QIMLDCWHRD PKERPRFAEL VEKLGDLLQA NVQQDGKDYI PINAILTGNS GFTYSTPAFS EDFFKESISA PKFNSGSSDD VRYVNAFKFM SLERIKTFEE LLPNATSMFD DYQGDSSTLL ASPMLKRFTW TDSKPKASLK IDLRVTSKSK ESGLSDVSRP SFCHSSCGHV SEGKRRFTYD HAELERKIAC CSPPPDYNSV VLYSTPPI