ID:VGFR3_HUMAN DESCRIPTION: RecName: Full=Vascular endothelial growth factor receptor 3; Short=VEGFR-3; EC=2.7.10.1; AltName: Full=Fms-like tyrosine kinase 4; Short=FLT-4; AltName: Full=Tyrosine-protein kinase receptor FLT4; Flags: Precursor; 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. INTERACTION: P35968:KDR; NbExp=3; IntAct=EBI-1005467, EBI-1005487; P49767:VEGFC; NbExp=2; IntAct=EBI-1005467, EBI-3405539; SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Cytoplasm. Nucleus. Note=Ligand-mediated autophosphorylation leads to rapid internalization. SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I membrane protein. Note=Ligand-mediated autophosphorylation leads to rapid internalization. SUBCELLULAR LOCATION: Isoform 2: Cell membrane; Single-pass type I membrane protein. SUBCELLULAR LOCATION: Isoform 3: Secreted. Cytoplasm. 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. PTM: Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation in response to H(2)O(2) is mediated by a process that requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is required for autophosphorylation at additional tyrosine residues. Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1 signaling pathways. In response to endothelial cell adhesion onto collagen, can also be phosphorylated in the absence of FLT4 kinase activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and Tyr-1337. DISEASE: Defects in FLT4 are the cause of lymphedema hereditary type 1A (LMPH1A) [MIM:153100]; also known as Nonne-Milroy lymphedema or Milroy disease. Hereditary lymphedema is 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: Defects in FLT4 are associated with susceptibility to hemangioma capillary infantile (HCI) [MIM:602089]. HCI are benign, highly proliferative lesions involving aberrant localized growth of capillary endothelium. They are the most common tumor of infancy, occurring in up to 10% of all births. Hemangiomas tend to appear shortly after birth and show rapid neonatal growth for up to 12 months characterized by endothelial hypercellularity and increased numbers of mast cells. This phase is followed by slow involution at a rate of about 10% per year and replacement by fibrofatty stroma. DISEASE: Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. SIMILARITY: Contains 7 Ig-like C2-type (immunoglobulin-like) domains. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=CAA48290.1; Type=Erroneous initiation; Note=Translation N-terminally shortened; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FLT4"; WEB RESOURCE: Name=Wikipedia; Note=FLT4 entry; URL="http://en.wikipedia.org/wiki/FLT4";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
SCOP Domains: 48726 - Immunoglobulin 56112 - Protein kinase-like (PK-like) 82895 - TSP-1 type 1 repeat
ModBase Predicted Comparative 3D Structure on P35916
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
BC027302 - Homo sapiens fms-related tyrosine kinase 4, mRNA (cDNA clone IMAGE:4212883). JD452055 - Sequence 433079 from Patent EP1572962. JD461074 - Sequence 442098 from Patent EP1572962. JD543504 - Sequence 524528 from Patent EP1572962. JD103580 - Sequence 84604 from Patent EP1572962. JD235097 - Sequence 216121 from Patent EP1572962. JD206981 - Sequence 188005 from Patent EP1572962. JD555111 - Sequence 536135 from Patent EP1572962. JD127063 - Sequence 108087 from Patent EP1572962. JD457974 - Sequence 438998 from Patent EP1572962. JD413060 - Sequence 394084 from Patent EP1572962. JD386161 - Sequence 367185 from Patent EP1572962. JD146842 - Sequence 127866 from Patent EP1572962. JD208448 - Sequence 189472 from Patent EP1572962. JD258686 - Sequence 239710 from Patent EP1572962. JD160402 - Sequence 141426 from Patent EP1572962. JD296750 - Sequence 277774 from Patent EP1572962. AY233383 - Homo sapiens VEGFR3 long form mRNA, complete cds; alternatively spliced. JD075266 - Sequence 56290 from Patent EP1572962. JD549291 - Sequence 530315 from Patent EP1572962. JD466227 - Sequence 447251 from Patent EP1572962. JD379347 - Sequence 360371 from Patent EP1572962. JD560265 - Sequence 541289 from Patent EP1572962. JD501379 - Sequence 482403 from Patent EP1572962. S66407 - FLT4=receptor tyrosine kinase isoform FLT4 long {3' region, alternatively spliced} [human, mRNA Partial, 216 nt]. BC167816 - Synthetic construct Homo sapiens clone IMAGE:100068206, MGC:195823 fms-related tyrosine kinase 4 (FLT4) mRNA, encodes complete protein. AY233382 - Homo sapiens VEGFR3 short form mRNA, complete cds; alternatively spliced. X69878 - H.sapiens Flt4 mRNA for transmembrane tyrosine kinase. AK309910 - Homo sapiens cDNA, FLJ99951. AB209637 - Homo sapiens mRNA for Vascular endothelial growth factor receptor 3 precursor variant protein. U43143 - Human receptor tyrosine kinase Flt4 (short form) mRNA, complete cds. X68203 - H.sapiens mRNA for FLT4, class III receptor tyrosine kinase. AK291679 - Homo sapiens cDNA FLJ76663 complete cds, highly similar to Homo sapiens fms-related tyrosine kinase 4 (FLT4), transcript variant 2, mRNA. EU826564 - Homo sapiens soluble VEGFR3 variant 1 (VEGFR3) mRNA, complete cds, alternatively spliced. EU826565 - Homo sapiens soluble VEGFR3 variant 2 (VEGFR3) mRNA, complete cds, alternatively spliced. EU826566 - Homo sapiens soluble VEGFR3 variant 3 (VEGFR3) mRNA, complete cds, alternatively spliced.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_no1Pathway - Actions of Nitric Oxide in the Heart h_vegfPathway - VEGF, Hypoxia, and Angiogenesis
Reactome (by CSHL, EBI, and GO)
Protein P35916 (Reactome details) participates in the following event(s):
R-HSA-194308 VEGF-C,D bind to VEGFR3 leading to receptor dimerization R-HSA-195399 VEGF binds to VEGFR leading to receptor dimerization R-HSA-194313 VEGF ligand-receptor interactions R-HSA-194138 Signaling by VEGF R-HSA-9006934 Signaling by Receptor Tyrosine Kinases R-HSA-162582 Signal Transduction
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
