O08775 (VGFR2_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Vascular endothelial growth factor receptor 2
Short name=VEGFR-2
EC=2.7.10.1

Alternative name(s):
Fetal liver kinase 1
Short name=FLK-1
Protein-tyrosine kinase receptor flk-1
CD_antigen=CD309

Gene names

Name:	Kdr
Synonyms:	Flk1

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	1343 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 haematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. 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 By similarity.
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 VEGFA, VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues By similarity.
Subunit structure	Interacts with VEGFA, VEGFC and VEGFD. Monomer in the absence of bound VEGFA, VEGFC or VEGFD. Homodimer in the presence of bound dimeric VEGFA, VEGFC or VEGFD. Can also form heterodimers with FLT1 and FLT4. Interacts (tyrosine phosphorylated) with FYN, NCK1, PLCG1 and SHB. Interacts with CBL. Interacts with SH2D2A/TSAD and GRB2. Interacts with MYOF By similarity.
Subcellular location	Cell membrane; Single-pass type I membrane protein By similarity. Cytoplasm By similarity. Nucleus By similarity. Cytoplasmic vesicle By similarity. Early endosome By similarity. Note: Detected on caveolae-enriched lipid rafts at the cell surface. Is recycled from the plasma membrane to endosomes and back again. Phosphorylation triggered by VEGFA binding promotes internalization and subsequent degradation. VEGFA binding triggers internalization and translocation to the nucleus By similarity.
Tissue specificity	Expressed in the post-pubertal mammary glands. Ref.2
Developmental stage	Increases during pregnancy (1.6-fold at 4 days) and lactation (3.8-fold at 7 days). Decreases in the early phases of involution (45%, 50% and 34% on days 1, 2, and 3 respectively). Ref.2
Domain	The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding By similarity.
Post-translational modification	N-glycosylated By similarity. Ubiquitinated. Tyrosine phosphorylation of the receptor promotes its poly-ubiquitination, leading to its degradation via the proteasome or lysosomal proteases By similarity. 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 at Tyr-947 is important for interaction with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin cytoskeleton. Phosphorylation at Tyr-1171 is important for interaction with PLCG1 and SHB. Phosphorylation at Tyr-1210 is important for interaction with NCK1 and FYN. Dephosphorylated by PTPRB. Dephosphorylated by PTPRJ at Tyr-797, Tyr-947, Tyr-992, Tyr-1050, Tyr-1055, Tyr-1171 and Tyr-1210 By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 7 Ig-like C2-type (immunoglobulin-like) domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Angiogenesis Differentiation
Cellular component	Cell membrane Cytoplasm Cytoplasmic vesicle Endosome Membrane Nucleus
Domain	Immunoglobulin domain Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW calcium-mediated signaling using intracellular calcium source Inferred from sequence or structural similarity. Source: UniProtKB elevation of cytosolic calcium ion concentration Inferred from mutant phenotype. Source: RGD embryonic hemopoiesis Inferred from sequence or structural similarity. Source: UniProtKB endothelium development Inferred from sequence or structural similarity. Source: UniProtKB male gonad development Inferred from direct assay. Source: RGD negative regulation of endothelial cell apoptosis Inferred from sequence or structural similarity. Source: UniProtKB neuron projection morphogenesis Inferred from mutant phenotype. Source: RGD neuroprotection Inferred from mutant phenotype. Source: RGD peptidyl-tyrosine phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of ERK1 and ERK2 cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of TOR signaling cascade Inferred from mutant phenotype. Source: RGD positive regulation of angiogenesis Inferred from direct assay. Source: RGD positive regulation of calcium-mediated signaling Inferred from mutant phenotype. Source: RGD positive regulation of cell migration Inferred from mutant phenotype. Source: RGD positive regulation of endothelial cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of long-term neuronal synaptic plasticity Inferred from mutant phenotype. Source: RGD positive regulation of nitric-oxide synthase biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of phosphatidylinositol 3-kinase cascade Inferred from mutant phenotype. Source: RGD positive regulation of vasodilation Inferred from genetic interaction. Source: RGD protein autophosphorylation Inferred from direct assay. Source: RGD response to hypoxia Inferred from mutant phenotype. Source: RGD vasculogenesis Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytoplasmic membrane-bounded vesicle Inferred from electronic annotation. Source: UniProtKB-SubCell early endosome Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB membrane fraction Inferred from direct assay. Source: RGD neuron projection Inferred from direct assay. Source: RGD neuronal cell body Inferred from direct assay. Source: RGD nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW growth factor binding Inferred from mutant phenotype. Source: RGD vascular endothelial growth factor-activated receptor activity Inferred from mutant phenotype. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 19	19	Potential
	Chain	20 – 1343	1324	Vascular endothelial growth factor receptor 2		PRO_0000016773
Regions
	Topological domain	20 – 760	741	Extracellular Potential
	Transmembrane	761 – 781	21	Helical; Potential
	Topological domain	782 – 1343	562	Cytoplasmic Potential
	Domain	46 – 109	64	Ig-like C2-type 1
	Domain	141 – 207	67	Ig-like C2-type 2
	Domain	224 – 320	97	Ig-like C2-type 3
	Domain	328 – 414	87	Ig-like C2-type 4
	Domain	421 – 540	120	Ig-like C2-type 5
	Domain	547 – 654	108	Ig-like C2-type 6
	Domain	663 – 749	87	Ig-like C2-type 7
	Domain	830 – 1158	329	Protein kinase
	Nucleotide binding	836 – 844	9	ATP By similarity
Sites
	Active site	1024	1	Proton acceptor By similarity
	Binding site	864	1	ATP By similarity
	Site	1171	1	Interaction with SHB By similarity
Amino acid modifications
	Modified residue	797	1	Phosphotyrosine By similarity
	Modified residue	947	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	992	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1050	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1055	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1171	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1210	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1301	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1305	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1315	1	Phosphotyrosine; by autocatalysis By similarity
	Glycosylation	46	1	N-linked (GlcNAc...) Potential
	Glycosylation	96	1	N-linked (GlcNAc...) Potential
	Glycosylation	143	1	N-linked (GlcNAc...) Potential
	Glycosylation	158	1	N-linked (GlcNAc...) Potential
	Glycosylation	245	1	N-linked (GlcNAc...) Potential
	Glycosylation	318	1	N-linked (GlcNAc...) Potential
	Glycosylation	374	1	N-linked (GlcNAc...) Potential
	Glycosylation	395	1	N-linked (GlcNAc...) Potential
	Glycosylation	507	1	N-linked (GlcNAc...) Potential
	Glycosylation	576	1	N-linked (GlcNAc...) Potential
	Glycosylation	609	1	N-linked (GlcNAc...) Potential
	Glycosylation	615	1	N-linked (GlcNAc...) Potential
	Glycosylation	627	1	N-linked (GlcNAc...) Potential
	Glycosylation	671	1	N-linked (GlcNAc...) Potential
	Glycosylation	700	1	N-linked (GlcNAc...) Potential
	Glycosylation	717	1	N-linked (GlcNAc...) Potential
	Disulfide bond	53 ↔ 103		By similarity
	Disulfide bond	150 ↔ 200		By similarity
	Disulfide bond	246 ↔ 307		By similarity
	Disulfide bond	445 ↔ 526		By similarity
	Disulfide bond	567 ↔ 638		By similarity
	Disulfide bond	684 ↔ 733		By similarity

Sequences

	Sequence		Length	Mass (Da)
	O08775 [UniParc]. Last modified July 1, 1997. Version 1. Checksum: AD7E509EB62D3FF4	FASTA	1,343	150,394
	10 20 30 40 50 60 MESRALLAVA LWFCVETRAA SVGLPGDSLH PPKLSTQKDI LTILANTTLQ ITCRGQRDLD 70 80 90 100 110 120 WLWPNTPRDS EERVLVTECG DSIFCKTLTV PRVVGNDTGA YKCFYRDTDV SSIVYVYVQD 130 140 150 160 170 180 HRSPFIASVS DEHGIVYITE NKNKTVVIPC RGSISNLNVS LCARYPEKRF VPDGNRISWD 190 200 210 220 230 240 SEKGFTIPSY MISYAGMVFC EAKINDETYQ SIMYIVLVVG YRIYDVVLSP PHEIELSAGE 250 260 270 280 290 300 KLVLNCTART ELNVGLDFSW QFPSSKHQHK KIVNRDVKSL PGTVAKMFLS TLTIDSVTKS 310 320 330 340 350 360 DQGEYTCTAY SGLMTKKNKT FVRVHTKPFI AFGSGMKSLV EATVGSQVRI PVKYLSYPAP 370 380 390 400 410 420 DIKWYRNGRP IESNYTMIVG DELTIMEVSE RDAGNYTVIL TNPISMEKQS HMVSLVVNVP 430 440 450 460 470 480 PQIGEKALIS PMDSYQYGTM QTLTCTVYAN PPLHHIQWYW QLEEACSYRP SQTNPYTCKE 490 500 510 520 530 540 WRHVKDFQGG NKIEVTKNQY ALIEGKNKTV STLVIQAAYV SALYKCEAIN KAGRGERVIS 550 560 570 580 590 600 FHVIRGPEIT VQPATQPTER ESMSLLCTAD RNTFENLTWY KLGSQATSVH MGESLTPVCK 610 620 630 640 650 660 NLDALWKLNG TVFSNSTNDI LIVAFQNASL QDQGNYVCSA QDKKTKKRHC LVKQLVILER 670 680 690 700 710 720 MAPMITGNLE NQTTTIGETI EVVCPTSGNP TPLITWFKDN ETLVEDSGIV LKDGNRNLTI 730 740 750 760 770 780 RRVRKEDGGL YTCQACNVLG CARAETLFII EGVQEKTNLE VIILVGTAVI AMFFWLLLVI 790 800 810 820 830 840 LVRTVKRANE GELKTGYLSI VMDPDELPLD ERCERLPYDA SKWEFPRDRL KLGKPLGRGA 850 860 870 880 890 900 FGQVIEADAF GIDKTATCKT VAVKMLKEGA THSEHRALMS ELKILIHIGH HLNVVNLLGA 910 920 930 940 950 960 CTKPGGPLMV IVEFCKFGNL STYLRGKRNE FVPYKSKGAR FRSGKDYVGE LSVDLKRRLD 970 980 990 1000 1010 1020 SITSSQSSAS SGFVEEKSLS DVEEEEASEE LYKDFLTLEH LICYSFQVAK GMEFLASRKC 1030 1040 1050 1060 1070 1080 IHRDLAARNI LLSEKNVVKI CDFGLARDIY KDPDYVRKGD PRLPLKWMAP ETIFDRIYTI 1090 1100 1110 1120 1130 1140 QSGVWSFGVL LWEIFSLGAS PYPGVKIDEK FCRRLKEGTR MRAPDYTTPE MYQTMLDCWH 1150 1160 1170 1180 1190 1200 EDPNQRPAFS ELVEHLGNLL QANAQQDGKD YIVLPMSETL SMEEDSGLSL PTSPVSCMEE 1210 1220 1230 1240 1250 1260 EEVCDPKFHY DNTAGISHYL QNSKRKSRPV SVKTFEDIPL EEPEVKVIPD DSQTDSGMVL 1270 1280 1290 1300 1310 1320 ASEELKTLED RNKLSPSFGG MMPSKSRESV ASEGSNQTSG YQSGYHSDDT DTTVYSSDEA 1330 1340 GLLKLVDVAG HVDSGTTLRS SPV

References

[1]	Wen Y., Edelman J.L., De Vries G.W., Sachs G. Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Retina.
[2]	"Regulation of VEGF and VEGF receptor expression in the rodent mammary gland during pregnancy, lactation, and involution." Pepper M.S., Baetens D., Mandriota S.J., Di Sanza C., Oikemus S., Lane T.F., Soriano J.V., Montesano R., Iruela-Arispe M.L. Dev. Dyn. 218:507-524(2000) [PubMed: 10878616] [Abstract] Cited for: TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
[3]	Lubec G., Kang S.U. Submitted (JUL-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 1040-1047, MASS SPECTROMETRY. Strain: Sprague-Dawley. Tissue: Brain.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U93306 mRNA. Translation: AAB97508.1. U93307 mRNA. Translation: AAB97509.1.
IPI	IPI00195682.
RefSeq	NP_037194.1. NM_013062.1.
UniGene	Rn.88869.
3D structure databases
ProteinModelPortal	O08775.
SMR	O08775. Positions 813-1167.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-7138598.
PTM databases
PhosphoSite	O08775.
Proteomic databases
PRIDE	O08775.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	25589.
KEGG	rno:25589.
Organism-specific databases
CTD	3791.
RGD	2965. Kdr.
Phylogenomic databases
HOVERGEN	HBG053432.
Enzyme and pathway databases
BRENDA	2.7.10.1. 5301.
Gene expression databases
Genevestigator	O08775.
Family and domain databases
InterPro	IPR007110. Ig-like. IPR013783. Ig-like_fold. IPR013098. Ig_I-set. IPR003599. Ig_sub. IPR003598. Ig_sub2. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase. IPR008266. Tyr_kinase_AS. IPR020635. Tyr_kinase_cat_dom. IPR001824. Tyr_kinase_rcpt_3_CS. IPR009136. Tyr_kinase_VEGFR2_rcpt. IPR009134. Tyr_kinase_VEGFR_rcpt_N. [Graphical view]
Gene3D	G3DSA:2.60.40.10. Ig-like_fold. 7 hits.
KO	K05098.
Pfam	PF07679. I-set. 3 hits. PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
PRINTS	PR01832. VEGFRECEPTOR. PR01834. VEGFRECEPTR2.
SMART	SM00409. IG. 5 hits. SM00408. IGc2. 1 hit. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS50835. IG_LIKE. 5 hits. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. PS00240. RECEPTOR_TYR_KIN_III. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	607259.

Entry information

Entry name

VGFR2_RAT

Accession

Primary (citable) accession number: O08775

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	July 1, 1997
Last modified:	January 25, 2012
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program