VGFR3_HUMAN » Vascular endothelial growth factor receptor 3

VGFR3_HUMAN » Vascular endothelial growth factor receptor 3
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Topology in Plasma membrane
Topologyextracellular side
cytoplasmic side
VGFR3_HUMAN » Vascular endothelial growth factor receptor 3 » VEGFR-3; Tyrosine-protein kinase receptor FLT4;
Hydrophobic Thickness 36.4 ± 1.4 Å
Tilt Angle 1 ± 0°
ΔGtransfer -46.2 kcal/mol
ΔGfold -24.9 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 774-799 (773-802)
Pathways

Cytokine-cytokine receptor interaction (KEGG)

Focal adhesion (KEGG)

PI3K-Akt signaling pathway (KEGG)

Signal Transduction (Reactome)

PDB 4bsk (A=23-229), 4bsj (A=330-553)
OPM none
Complexes none
Interactions

ITA5, Complex: ITA5:VGFR3, PubMed

ITB1, Complex: ITB1:VGFR3, PubMed

NRP2, Complex: VGFR3:NRP2

VGFR2, Complex: VGFR2:VGFR3, PubMed

Domains

AA: 231-314, PDBID: 1RY7, Subunit B, Seq Identity:28%, Immunoglobulin domain

AA: 558-657, PDBID: 2OM5, Subunit A, Seq Identity:23%, Immunoglobulin domain

AA: 678-765, PDBID: 3KVQ, Subunit A, Seq Identity:36%, Immunoglobulin I-set domain

AA: 845-1169, PDBID: 1VR2, Subunit A, Seq Identity:76%, Protein tyrosine kinase

UniProt annotation for VGFR3_HUMAN » Vascular endothelial growth factor receptor 3
FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3- kinase. Promotes phosphorylation of MAPK8 at "Thr-183" and "Tyr- 185", and of AKT1 at "Ser-473".

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 VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by MAZ51.

SUBUNIT: Interacts with VEGFC and VEGFD. Monomer in the absence of bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the interaction is enhanced by stimulation with VEGFC. Interacts with CRK, GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP- 2. Identified in a complex with SRC and ITGB1.

TISSUE SPECIFICITY: Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney.

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

DISEASE: Lymphedema, hereditary, 1A (LMPH1A) OMIM: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. disease is caused by mutations affecting the gene represented in this entry.

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. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.

DISEASE: Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.

UniProt features for VGFR3_HUMAN » Vascular endothelial growth factor receptor 3
SIGNAL 1 24
CHAIN 25 1363 Vascular endothelial growth factor receptor 3.
DOMAIN 30 127 Ig-like C2-type 1.
DOMAIN 151 213 Ig-like C2-type 2.
DOMAIN 219 326 Ig-like C2-type 3.
DOMAIN 331 415 Ig-like C2-type 4.
DOMAIN 422 552 Ig-like C2-type 5.
DOMAIN 555 671 Ig-like C2-type 6.
DOMAIN 678 764 Ig-like C2-type 7.
DOMAIN 845 1173 Protein kinase.
ACT_SITE 1037 1037 Proton acceptor (By similarity).
DISULFID 51 111 By similarity.
DISULFID 158 206 By similarity.
DISULFID 252 310 By similarity.
DISULFID 445 534 By similarity.
DISULFID 578 653 By similarity.
DISULFID 699 751 By similarity.
Amino Acid Sequence for VGFR3_HUMAN » Vascular endothelial growth factor receptor 3
MQRGAALCLR LWLCLGLLDG LVSGYSMTPP TLNITEESHV IDTGDSLSIS CRGQHPLEWA WPGAQEAPAT GDKDSEDTGV VRDCEGTDAR PYCKVLLLHE VHANDTGSYV CYYKYIKARI EGTTAASSYV FVRDFEQPFI NKPDTLLVNR KDAMWVPCLV SIPGLNVTLR SQSSVLWPDG QEVVWDDRRG MLVSTPLLHD ALYLQCETTW GDQDFLSNPF LVHITGNELY DIQLLPRKSL ELLVGEKLVL NCTVWAEFNS GVTFDWDYPG KQAERGKWVP ERRSQQTHTE LSSILTIHNV SQHDLGSYVC KANNGIQRFR ESTEVIVHEN PFISVEWLKG PILEATAGDE LVKLPVKLAA YPPPEFQWYK DGKALSGRHS PHALVLKEVT EASTGTYTLA LWNSAAGLRR NISLELVVNV PPQIHEKEAS SPSIYSRHSR QALTCTAYGV PLPLSIQWHW RPWTPCKMFA QRSLRRRQQQ DLMPQCRDWR AVTTQDAVNP IESLDTWTEF VEGKNKTVSK LVIQNANVSA MYKCVVSNKV GQDERLIYFY VTTIPDGFTI ESKPSEELLE GQPVLLSCQA DSYKYEHLRW YRLNLSTLHD AHGNPLLLDC KNVHLFATPL AASLEEVAPG ARHATLSLSI PRVAPEHEGH YVCEVQDRRS HDKHCHKKYL SVQALEAPRL TQNLTDLLVN VSDSLEMQCL VAGAHAPSIV WYKDERLLEE KSGVDLADSN QKLSIQRVRE EDAGRYLCSV CNAKGCVNSS ASVAVEGSED KGSMEIVILV GTGVIAVFFW VLLLLIFCNM RRPAHADIKT GYLSIIMDPG EVPLEEQCEY LSYDASQWEF PRERLHLGRV LGYGAFGKVV EASAFGIHKG SSCDTVAVKM LKEGATASEH RALMSELKIL IHIGNHLNVV NLLGACTKPQ GPLMVIVEFC KYGNLSNFLR AKRDAFSPCA EKSPEQRGRF RAMVELARLD RRRPGSSDRV LFARFSKTEG GARRASPDQE AEDLWLSPLT MEDLVCYSFQ VARGMEFLAS RKCIHRDLAA RNILLSESDV VKICDFGLAR DIYKDPDYVR KGSARLPLKW MAPESIFDKV YTTQSDVWSF GVLLWEIFSL GASPYPGVQI NEEFCQRLRD GTRMRAPELA TPAIRRIMLN CWSGDPKARP AFSELVEILG DLLQGRGLQE EEEVCMAPRS SQSSEEGSFS QVSTMALHIA QADAEDSPPS LQRHSLAARY YNWVSFPGCL ARGAETRGSS RMKTFEEFPM TPTTYKGSVD NQTDSGMVLA SEEFEQIESR HRQESGFR