Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

FLT4 (P35916) - Overview - Molecular Target Synopsis

Protein


FLT4, Vascular endothelial growth factor receptor 3
Enzyme Classification 2.7.10.1
UniProt P35916

Also Known as VGFR3_HUMAN, FLT4, VEGFR3

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'. 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.

4BSK
CRYSTAL STRUCTURE OF VEGF-C IN COMPLEX WITH VEGFR-3 DOMAINS D1-2
RCSB/PDB
Inspect Structure
See all 3D Structures for FLT4

Isoforms / Transcripts (Protein Coding)


Drugs


FLT4 is targeted by Approved Drugs Axitinib, Sunitinib, Sorafenib, Pazopanib, Vandetanib. (see details)
Axitinib
Sunitinib
Sorafenib
Pazopanib
Vandetanib

Sub-cellular localization


UniProt: FLT4 is active in the following subcellular-locations: cell membrane, cytoplasm, nucleus, secreted.
GO terms: FLT4 is active in the following subcellular-locations: cytoplasm, extracellular region, integral component of plasma membrane, nucleoplasm, plasma membrane, receptor complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project FLT4 has gain in 3 cell-lines, loss in 3 cell-lines and no signal in 999 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: DU_145, HS578T, NCI_ADR_RES

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: UKE-1, NCI-H1930, HCC12

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: HUVEC, SK-N-SH, NHLF

(see details)

RNA Interference


FLT4 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: CAL120, MHM. (see details)

3D Structures


For FLT4 there are:
2 structures (2 chains) solved
2 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


FLT4 has been screened with 1484 compounds (2284 bioactivities), 340 compounds have bioactivities that show binding affinity of <= 500nM (419 bioactivities). (see details)