InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: FLT4

Summary

InnateDB Protein

IDBP-62357.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

FLT4

Protein Name

fms-related tyrosine kinase 4

Synonyms

FLT41; LMPH1A; PCL; VEGFR3;

Species

Homo sapiens

Ensembl Protein

ENSP00000261937

InnateDB Gene

IDBG-62355 (FLT4)

Protein Structure

UniProt Annotation

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'. {ECO:0000269PubMed:11532940, ECO:0000269PubMed:15102829, ECO:0000269PubMed:15474514, ECO:0000269PubMed:16076871, ECO:0000269PubMed:16452200, ECO:0000269PubMed:17210781, ECO:0000269PubMed:19610651, ECO:0000269PubMed:19779139, ECO:0000269PubMed:20224550, ECO:0000269PubMed:20431062, ECO:0000269PubMed:20445537, ECO:0000269PubMed:21273538, ECO:0000269PubMed:7675451, ECO:0000269PubMed:8700872, ECO:0000269PubMed:9435229}.

Subcellular Localization

Cell membrane; Single-pass type I membrane protein. Cytoplasm. Nucleus. Note=Ligand-mediated autophosphorylation leads to rapid internalization.Isoform 1: Cell membrane; Single-pass type I membrane protein. Note=Ligand-mediated autophosphorylation leads to rapid internalization.Isoform 2: Cell membrane; Single-pass type I membrane protein.Isoform 3: Secreted. Cytoplasm.

Disease Associations

Lymphedema, hereditary, 1A (LMPH1A) [MIM:153100]: 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. {ECO:0000269PubMed:10835628, ECO:0000269PubMed:10856194, ECO:0000269PubMed:9817924}. Note=The disease is caused by mutations affecting the gene represented in this entry.Hemangioma, capillary infantile (HCI) [MIM:602089]: 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. {ECO:0000269PubMed:11807987}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.Note=Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.

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. {ECO:0000269PubMed:1327515, ECO:0000269PubMed:20224550, ECO:0000269PubMed:7675451}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 17 experimentally validated interaction(s) in this database.
They are also associated with 4 interaction(s) predicted by orthology.

Experimentally validated
Total	17 [view]
Protein-Protein	17 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	4 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0005021	vascular endothelial growth factor-activated receptor activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0019838	growth factor binding
GO:0019903	protein phosphatase binding

Biological Process

GO:0001934	positive regulation of protein phosphorylation
GO:0001938	positive regulation of endothelial cell proliferation
GO:0001944	vasculature development
GO:0001945	lymph vessel development
GO:0001946	lymphangiogenesis
GO:0002040	sprouting angiogenesis
GO:0006468	protein phosphorylation
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0008284	positive regulation of cell proliferation
GO:0010575	positive regulation vascular endothelial growth factor production
GO:0010595	positive regulation of endothelial cell migration
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0035924	cellular response to vascular endothelial growth factor stimulus
GO:0043066	negative regulation of apoptotic process
GO:0043410	positive regulation of MAPK cascade
GO:0045087	innate immune response (InnateDB)
GO:0046330	positive regulation of JNK cascade
GO:0046777	protein autophosphorylation
GO:0048010	vascular endothelial growth factor receptor signaling pathway
GO:0048514	blood vessel morphogenesis
GO:0060312	regulation of blood vessel remodeling
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:0090037	positive regulation of protein kinase C signaling

Cellular Component

GO:0005576	extracellular region
GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0043235	receptor complex

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR003598 Immunoglobulin subtype 2
IPR003599 Immunoglobulin subtype
IPR007110 Immunoglobulin-like domain
IPR009137 Vascular endothelial growth factor receptor 3 (VEGFR3)
IPR011009 Protein kinase-like domain
IPR013098 Immunoglobulin I-set
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF07679

PRINTS

PR00109
PR01835

PIRSF

SMART

SM00220
SM00408
SM00409
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt