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
RNA Interference
Mutations

KDR (P35968) - Overview - Molecular Target Synopsis

Protein


KDR, Vascular endothelial growth factor receptor 2
Enzyme Classification 2.7.10.1
UniProt P35968

Also Known as VGFR2_HUMAN, KDR, FLK1, VEGFR2

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. 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:10102632, PubMed:10590123, PubMed:12649282, PubMed:12881528, PubMed:1417831, PubMed:15026417, PubMed:15215251, PubMed:15837294, PubMed:15962004, PubMed:16966330, PubMed:17253678, PubMed:18529047, PubMed:18593464, PubMed:19033661, PubMed:19668192, PubMed:20080685, PubMed:20145116, PubMed:20224550, PubMed:20705758, PubMed:21827946, PubMed:21893193, PubMed:9160888). 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:23529610).

5EW3 deposition date (2015-11-20)
HUMAN VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 (KDR) KINASE DOMAIN IN COMPLEX WITH AAL993
RCSB/PDB
Inspect Structure
See all 3D Structures for KDR

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
1356ENSG00000128052ENST00000263923ENSP00000263923P35968-1
712P35968-3
678P35968-2

Drugs


KDR is targeted by Approved Drugs Sj000057774, Vandetanib, Sorafenib Tosylate, Sunitinib Malate, Axitinib, Pazopanib, Ramucirumab. (see details)

Sub-cellular localization


UniProt: KDR is active in the following subcellular-locations: Cell junction, Cell membrane, Cytoplasm, Cytoplasmic vesicle, Early endosome, Endoplasmic reticulum, Nucleus, Secreted.
GO terms: KDR is active in the following subcellular-locations: cell junction, cytoplasmic, early endosome, endoplasmic reticulum, endosome, extracellular region, Golgi apparatus, integral component of plasma membrane, membrane raft, nucleus, plasma membrane, sorting endosome.



UniProt
GO terms

Mutations in Cancer


Please click the link to see mutations reported in COSMIC - Cell Lines Project
Please click the link to see mutations reported in COSMIC
KDR has somatic mutations in these tumour types NSCLC, angiosarcoma"
Please click the link to see mutations reported in ICGC
(see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MDA_MB_435, SNB_19, MCF7

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: OCI-M2, NCI-H226, TYK-nu.CP-r

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, H1-hESC, SK-N-SH

(see details)

RNA Interference


KDR was reported in the following RNAI studies:

AACR Journals - Results of primary druggable genome v2 (DG2) Achilles heel siRNA screen in KMS11 multiple myeloma cells, the highest RNAi cell lines are: KMS11. (see details)

Broad Institute - Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1, the highest RNAi cell lines are: MDAMB453, NOMO1. (see details)

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: COV504, KPD. (see details)

3D Structures


There are 47 structures (64 chains) solved for KDR
39 are solved in complex with at least one small molecule ligand
5 are solved with an approved drug

KDR is solved in complex with the approved drug(s) ADN/Adenosine (4CKI_A,4CKJ_A), BAX/Sorafenib (3WZE_A,4ASD_A), 0LI/Ponatinib (4QRC_A,4TYJ_A,4U0I_A,4UXQ_A,4V01_A,4V01_B,4V04_A,4V04_B), ZD6/Vandetanib (2IVU_A), B49/Sunitinib (3G0E_A,3G0F_A,3G0F_B,4AGD_A), AXI/Axitinib (4AG8_A,4AGC_A) and STI/Imatinib,Imatinib mesylate (1T46_A,4R7I_A).
(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


KDR has been screened with 7044 compounds (10646 bioactivities), 3065 compounds have bioactivities that show binding affinity of <= 500nM (4524 bioactivities). (see details)