VGFR2_HUMAN » Vascular endothelial growth factor receptor 2

VGFR2_HUMAN » Vascular endothelial growth factor receptor 2
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
VGFR2_HUMAN » Vascular endothelial growth factor receptor 2 » VEGFR-2; Kinase insert domain receptor;Protein-tyrosine kinase receptor Flk-1;
Hydrophobic Thickness 36.8 ± 3.2 Å
Tilt Angle 6 ± 2°
ΔGtransfer -48.6 kcal/mol
ΔGfold -25.4 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 760-789 (757-792)
Pathways

Bevacizumab Pathway (SMPDB)

Cytokine-cytokine receptor interaction (KEGG)

Endocytosis (KEGG)

Focal adhesion (KEGG)

PI3K-Akt signaling pathway (KEGG)

Proteoglycans in cancer (KEGG)

Signal Transduction (Reactome)

Vatalanib Pathway (SMPDB)

VEGF signaling pathway (KEGG)

PDB 4ase (787-1171), 4agc (787-1171), 4agd (787-1171), 4asd (787-1171), 3cjg (806-1168), 3cjf (806-1168), 3vhk (806-1171), 3vnt (806-1171), 2xir (806-1171), 1vr2 (806-1171), 4ag8 (806-1171), 2oh4 (806-1171), 3vo3 (806-1171), 1ywn (806-1171), 1y6b (806-1171), 1y6a (806-1171), 3c7q (806-1171), 3vhe (811-1169), 3vid (813-1168), 3ewh (815-1171), 3u6j (815-1171), 2qu5 (815-1171), 3efl (815-1171), 3dtw (815-1171), 3cpc (815-1171), 3cpb (815-1171), 2rl5 (815-1171), 3b8q (815-1171), 2p2i (815-1171), 3b8r (815-1171), 2p2h (815-1171), 3be2 (815-1171), 3cp9 (815-1171), 2qu6 (815-1171), 2met (A/B/C=759-795), 2meu (A/B=759-795), 2m59 (A/B=759-795), 3kvq (A=657-764), 2x1w (L/M/N/O=120-326), 2x1x (R=120-326), 3v6b (R=132-548), 3v2a (R=2-764), 3s37 (X=220-338), 3s36 (X=220-338), 3s35 (X=220-338)
OPM 2m59, 2met, 2meu
Complexes

VGFR2:VGFR2_HUMAN

Interactions

CADH5, Complex: VGFR2:CADH5, PubMed

IL3RB, Complex: VGFR2:IL3RB, PubMed

ITA2, Complex: VGFR2:ITA2

ITB3, Complex: ITB3:VGFR2, PubMed

MET, Complex: MET:VGFR2, PubMed

NRP1, Complex: NRP1:VGFR2, PubMed

NRP1, Complex: VGFR2:VEGFA:NRP1

PLXA1, Complex: VGFR2:PLXA1, PubMed

PTPRJ, Complex: VGFR2:PTPRJ, PubMed

VGFR1, Complex: VGFR1:VGFR2, PubMed

VGFR2, Complex: Transmembrane homodimer of vascular endothelial growth factor receptor 2, PDBID: 2M59

VGFR3, Complex: VGFR2:VGFR3, PubMed

Domains

AA: 229-321, PDBID: 2X1W, Subunit L, Seq Identity:100%, Immunoglobulin domain

AA: 333-417, PDBID: 3MTR, Subunit A, Seq Identity:33%, Immunoglobulin I-set domain

AA: 550-646, PDBID: 1RY7, Subunit B, Seq Identity:23%, Immunoglobulin domain

AA: 667-754, PDBID: 3KVQ, Subunit A, Seq Identity:100%, Immunoglobulin I-set domain

AA: 834-1160, PDBID: 1VR2, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for VGFR2_HUMAN » Vascular endothelial growth factor receptor 2
FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.

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, VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by the small molecule PTK inhibitor SU5614 ((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3- dihydro-2H-indol-2-one). May be regulated by hydrogen sulfide (H(2)S) levels via a H(2)S-sensitive intracellular disulfide bond.

SUBUNIT: Homodimer in the presence of bound dimeric VEGFA, VEGFC or VEGFD ligands; monomeric in the absence of bound ligands. Can also form heterodimers with FLT1/VEGFR1 and FLT4/VEGFR2. Interacts (tyrosine phosphorylated) with LFYN, NCK1, PLCG1. Interacts (tyrosine-phosphorylated active form preferentially) with DAB2IP (via C2 domain and active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts with SHBSH2D2A/TSAD, GRB2, MYOF, CBL and PDCD6. Interacts with HIV-1 Tat (PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed, PubMed). Interacts (via C-terminus domain) with ERN1 (via kinase domain); the interaction is facilitated in a XBP1 isoform 1- and vascular endothelial growth factor (VEGF)-dependent manner in endothelial cells (PubMed).

TISSUE SPECIFICITY: Detected in cornea (at protein level). Widely expressed.

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

DISEASE: Hemangioma, capillary infantile (HCI) OMIM: A condition characterized by dull red, firm, dome-shaped hemangiomas, sharply demarcated from surrounding skin, usually presenting at birth or occurring within the first two or three months of life. They result from highly proliferative, localized growth of capillary endothelium and generally undergo regression and involution without scarring. associated with variations affecting the gene represented in this entry.

DISEASE: Note=Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi"s sarcoma lesions.

UniProt features for VGFR2_HUMAN » Vascular endothelial growth factor receptor 2
SIGNAL 1 19 Potential.
CHAIN 20 1356 Vascular endothelial growth factor receptor 2.
DOMAIN 46 110 Ig-like C2-type 1.
DOMAIN 141 207 Ig-like C2-type 2.
DOMAIN 224 320 Ig-like C2-type 3.
DOMAIN 328 414 Ig-like C2-type 4.
DOMAIN 421 548 Ig-like C2-type 5.
DOMAIN 551 660 Ig-like C2-type 6.
DOMAIN 667 753 Ig-like C2-type 7.
DOMAIN 834 1162 Protein kinase.
ACT_SITE 1028 1028 Proton acceptor (By similarity).
SITE 1175 1175 Interaction with SHB (By similarity).
DISULFID 53 103 By similarity.
DISULFID 150 200
DISULFID 246 307
DISULFID 445 530 By similarity.
DISULFID 571 642 By similarity.
DISULFID 688 737 By similarity.
Amino Acid Sequence for VGFR2_HUMAN » Vascular endothelial growth factor receptor 2
MQSKVLLAVA LWLCVETRAA SVGLPSVSLD LPRLSIQKDI LTIKANTTLQ ITCRGQRDLD WLWPNNQSGS EQRVEVTECS DGLFCKTLTI PKVIGNDTGA YKCFYRETDL ASVIYVYVQD YRSPFIASVS DQHGVVYITE NKNKTVVIPC LGSISNLNVS LCARYPEKRF VPDGNRISWD SKKGFTIPSY MISYAGMVFC EAKINDESYQ SIMYIVVVVG YRIYDVVLSP SHGIELSVGE KLVLNCTART ELNVGIDFNW EYPSSKHQHK KLVNRDLKTQ SGSEMKKFLS TLTIDGVTRS DQGLYTCAAS SGLMTKKNST FVRVHEKPFV AFGSGMESLV EATVGERVRI PAKYLGYPPP EIKWYKNGIP LESNHTIKAG HVLTIMEVSE RDTGNYTVIL TNPISKEKQS HVVSLVVYVP PQIGEKSLIS PVDSYQYGTT QTLTCTVYAI PPPHHIHWYW QLEEECANEP SQAVSVTNPY PCEEWRSVED FQGGNKIEVN KNQFALIEGK NKTVSTLVIQ AANVSALYKC EAVNKVGRGE RVISFHVTRG PEITLQPDMQ PTEQESVSLW CTADRSTFEN LTWYKLGPQP LPIHVGELPT PVCKNLDTLW KLNATMFSNS TNDILIMELK NASLQDQGDY VCLAQDRKTK KRHCVVRQLT VLERVAPTIT GNLENQTTSI GESIEVSCTA SGNPPPQIMW FKDNETLVED SGIVLKDGNR NLTIRRVRKE DEGLYTCQAC SVLGCAKVEA FFIIEGAQEK TNLEIIILVG TAVIAMFFWL LLVIILRTVK RANGGELKTG YLSIVMDPDE LPLDEHCERL PYDASKWEFP RDRLKLGKPL GRGAFGQVIE ADAFGIDKTA TCRTVAVKML KEGATHSEHR ALMSELKILI HIGHHLNVVN LLGACTKPGG PLMVIVEFCK FGNLSTYLRS KRNEFVPYKT KGARFRQGKD YVGAIPVDLK RRLDSITSSQ SSASSGFVEE KSLSDVEEEE APEDLYKDFL TLEHLICYSF QVAKGMEFLA SRKCIHRDLA ARNILLSEKN VVKICDFGLA RDIYKDPDYV RKGDARLPLK WMAPETIFDR VYTIQSDVWS FGVLLWEIFS LGASPYPGVK IDEEFCRRLK EGTRMRAPDY TTPEMYQTML DCWHGEPSQR PTFSELVEHL GNLLQANAQQ DGKDYIVLPI SETLSMEEDS GLSLPTSPVS CMEEEEVCDP KFHYDNTAGI SQYLQNSKRK SRPVSVKTFE DIPLEEPEVK VIPDDNQTDS GMVLASEELK TLEDRTKLSP SFGGMVPSKS RESVASEGSN QTSGYQSGYH SDDTDTTVYS SEEAELLKLI EIGVQTGSTA QILQPDSGTT LSSPPV