P35969 (VGFR1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Vascular endothelial growth factor receptor 1
Short name=VEGFR-1
EC=2.7.10.1

Alternative name(s):
Embryonic receptor kinase 2
Fms-like tyrosine kinase 1
Short name=FLT-1
Tyrosine-protein kinase receptor FLT

Gene names

Name:	Flt1
Synonyms:	Emrk2, Flt, Vegfr1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1333 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, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, and proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts. Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to the activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC, YES1 and PLCG, and may also phosphorylate CBL. Promotes phosphorylation of AKT1 and PTK2/FAK1 By similarity. Ref.5 Ref.6 Ref.7 Ref.8 Ref.10 Ref.11
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, VEGFB or PGF leads to dimerization and activation by autophosphorylation on tyrosine residues By similarity.
Subunit structure	Interacts with VEGFA, VEGFB and PGF. Monomer in the absence of bound VEGFA, VEGFB or PGF. Homodimer in the presence of bound VEGFA, VEGFB and PGF. Can also form a heterodimer with KDR. Interacts (tyrosine phosphorylated) with CBL, CRK, GRB2, NCK1, PIK3R1, PLCG, PSEN1 and PTPN11. Probably interacts with PTPRB. Interacts with GNB2L1/RACK1. Identified in a complex with CBL and CD2AP By similarity.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Endosome By similarity. Note: Autophosphorylation promotes ubiquitination and endocytosis By similarity.
Domain	The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFA binding By similarity.
Post-translational modification	N-glycosylated By similarity. Ubiquitinated after VEGFA-mediated autophosphorylation, leading to proteolytic degradation 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-1169 is important for interaction with PLCG. Phosphorylation at Tyr-1213 is important for interaction with PIK3R1, PTPN11, GRB2, and PLCG. Phosphorylation at Tyr-1328 is important for endocytosis and for interaction with CBL, NCK1 and CRK. Is probably dephosphorylated by PTPRB By similarity.
Disruption phenotype	Embryonic lethality at about 9 dpc, due to defects in the formation and organization of the vascular network. Mice display abnormal blood island structures in the yolk sac, leading to defects in the organization of the vascular endothelium, excess growth and disorganization of embryonic and extraembryonic vasculature, including the endocardium and the microvasculature. Mice expressing a mutant protein that lacks the kinase domain survive and have no apparent phenotype. Ref.5 Ref.6 Ref.8
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 Chemotaxis Differentiation
Cellular component	Cell membrane Endosome Membrane
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	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW cell migration Inferred from mutant phenotype Ref.6. Source: UniProtKB embryonic morphogenesis Inferred from mutant phenotype Ref.5. Source: UniProtKB monocyte chemotaxis Inferred from electronic annotation. Source: Compara patterning of blood vessels Inferred from mutant phenotype Ref.8. Source: MGI peptidyl-tyrosine phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of MAP kinase activity Inferred from electronic annotation. Source: Compara positive regulation of angiogenesis Inferred from electronic annotation. Source: Compara positive regulation of cell migration Inferred from electronic annotation. Source: Compara positive regulation of phosphatidylinositol 3-kinase activity Inferred from electronic annotation. Source: Compara positive regulation of phosphatidylinositol 3-kinase cascade Inferred from electronic annotation. Source: Compara positive regulation of phospholipase C activity Inferred from electronic annotation. Source: Compara positive regulation of vascular endothelial growth factor receptor signaling pathway Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB sprouting angiogenesis Inferred from mutant phenotype PubMed 19758562. Source: MGI vascular endothelial growth factor receptor signaling pathway Inferred from mutant phenotype Ref.6. Source: MGI
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: Compara endosome Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW VEGF-A-activated receptor activity Inferred from electronic annotation. Source: Compara VEGF-B-activated receptor activity Inferred from electronic annotation. Source: Compara placental growth factor-activated receptor activity Inferred from electronic annotation. Source: Compara vascular endothelial growth factor-activated receptor activity Inferred from direct assay PubMed 8356051. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 22	22	Potential
	Chain	23 – 1333	1311	Vascular endothelial growth factor receptor 1		PRO_0000016769
Regions
	Topological domain	23 – 759	737	Extracellular Potential
	Transmembrane	760 – 781	22	Helical; Potential
	Topological domain	782 – 1333	552	Cytoplasmic Potential
	Domain	32 – 124	93	Ig-like C2-type 1
	Domain	152 – 215	64	Ig-like C2-type 2
	Domain	231 – 328	98	Ig-like C2-type 3
	Domain	334 – 429	96	Ig-like C2-type 4
	Domain	430 – 550	121	Ig-like C2-type 5
	Domain	557 – 656	100	Ig-like C2-type 6
	Domain	662 – 748	87	Ig-like C2-type 7
	Domain	828 – 1158	331	Protein kinase
	Nucleotide binding	834 – 842	9	ATP By similarity
Sites
	Active site	1022	1	Proton acceptor By similarity
	Binding site	862	1	ATP By similarity
	Site	768 – 769	2	Cleavage; by PSEN1 By similarity
Amino acid modifications
	Modified residue	915	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1053	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1169	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1213	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1242	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1263	1	Phosphothreonine Ref.9
	Modified residue	1322	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1328	1	Phosphotyrosine; by autocatalysis By similarity
	Glycosylation	101	1	N-linked (GlcNAc...) Potential
	Glycosylation	165	1	N-linked (GlcNAc...) Potential
	Glycosylation	197	1	N-linked (GlcNAc...) Potential
	Glycosylation	252	1	N-linked (GlcNAc...) Potential
	Glycosylation	324	1	N-linked (GlcNAc...) Potential
	Glycosylation	418	1	N-linked (GlcNAc...) Potential
	Glycosylation	475	1	N-linked (GlcNAc...) Potential
	Glycosylation	517	1	N-linked (GlcNAc...) Potential
	Glycosylation	598	1	N-linked (GlcNAc...) Potential
	Glycosylation	626	1	N-linked (GlcNAc...) Potential
	Glycosylation	667	1	N-linked (GlcNAc...) Potential
	Glycosylation	714	1	N-linked (GlcNAc...) Potential
	Disulfide bond	53 ↔ 108		By similarity
	Disulfide bond	159 ↔ 208		By similarity
	Disulfide bond	253 ↔ 312		By similarity
	Disulfide bond	455 ↔ 536		By similarity
	Disulfide bond	578 ↔ 637		By similarity
	Disulfide bond	683 ↔ 732		By similarity
Experimental info
	Sequence conflict	158	1	Missing in CAA55311. Ref.2
	Sequence conflict	211	1	Missing in CAA55311. Ref.2
	Sequence conflict	245	1	H → L in CAA55311. Ref.2
	Sequence conflict	603	1	H → N in CAA55311. Ref.2
	Sequence conflict	609 – 615	7	KMATTQD → NGHHSS in CAA55311. Ref.2
	Sequence conflict	696	1	F → L in CAA55311. Ref.2
	Sequence conflict	734	1	A → S in CAA55311. Ref.2
	Sequence conflict	765	1	C → Y in CAA55311. Ref.2
	Sequence conflict	820	1	K → N in CAA55311. Ref.2
	Sequence conflict	1009	1	G → R in CAA55311. Ref.2
	Sequence conflict	1181	1	S → G in BAA24498. Ref.3
	Sequence conflict	1181	1	S → N in CAA55311. Ref.2
	Sequence conflict	1193 – 1194	2	LF → RG in CAA55311. Ref.2
	Sequence conflict	1278 – 1279	2	KS → PR in CAA55311. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P35969 [UniParc]. Last modified June 1, 1994. Version 1. Checksum: C06533B7ECBC404C	FASTA	1,333	149,876
	10 20 30 40 50 60 MVSCWDTAVL PYALLGCLLL TGYGSGSKLK VPELSLKGTQ HVMQAGQTLF LKCRGEAAHS 70 80 90 100 110 120 WSLPTTVSQE DKRLSITPPS ACGRDNRQFC STLTLDTAQA NHTGLYTCRY LPTSTSKKKK 130 140 150 160 170 180 AESSIYIFVS DAGSPFIEMH TDIPKLVHMT EGRQLIIPCR VTSPNVTVTL KKFPFDTLTP 190 200 210 220 230 240 DGQRITWDSR RGFIIANATY KEIGLLNCEA TVNGHLYQTN YLTHRQTNTI LDVQIRPPSP 250 260 270 280 290 300 VRLLHGQTLV LNCTATTELN TRVQMSWNYP GKATKRASIR QRIDRSHSHN NVFHSVLKIN 310 320 330 340 350 360 NVESRDKGLY TCRVKSGSSF QSFNTSVHVY EKGFISVKHR KQPVQETTAG RRSYRLSMKV 370 380 390 400 410 420 KAFPSPEIVW LKDGSPATLK SARYLVHGYS LIIKDVTTED AGDYTILLGI KQSRLFKNLT 430 440 450 460 470 480 ATLIVNVKPQ IYEKSVSSLP SPPLYPLGSR QVLTCTVYGI PRPTITWLWH PCHHNHSKER 490 500 510 520 530 540 YDFCTENEES FILDPSSNLG NRIESISQRM TVIEGTNKTV STLVVADSQT PGIYSCRAFN 550 560 570 580 590 600 KIGTVERNIK FYVTDVPNGF HVSLEKMPAE GEDLKLSCVV NKFLYRDITW ILLRTVNNRT 610 620 630 640 650 660 MHHSISKQKM ATTQDYSITL NLVIKNVSLE DSGTYACRAR NIYTGEDILR KTEVLVRDSE 670 680 690 700 710 720 APHLLQNLSD YEVSISGSTT LDCQARGVPA PQITWFKNNH KIQQEPGIIL GPGNSTLFIE 730 740 750 760 770 780 RVTEEDEGVY RCRATNQKGA VESAAYLTVQ GTSDKSNLEL ITLTCTCVAA TLFWLLLTLF 790 800 810 820 830 840 IRKLKRSSSE VKTDYLSIIM DPDEVPLDEQ CERLPYDASK WEFARERLKL GKSLGRGAFG 850 860 870 880 890 900 KVVQASAFGI KKSPTCRTVA VKMLKEGATA SEYKALMTEL KILTHIGHHL NVVNLLGACT 910 920 930 940 950 960 KQGGPLMVIV EYCKYGNLSN YLKSKRDLFC LNKDAALHME LKKESLEPGL EQGQKPRLDS 970 980 990 1000 1010 1020 VSSSSVTSSS FPEDRSVSDV EGDEDYSEIS KQPLTMEDLI SYSFQVARGM EFLSSRKCIH 1030 1040 1050 1060 1070 1080 RDLAARNILL SENNVVKICD FGLARDIYKN PDYVRRGDTR LPLKWMAPES IFDKVYSTKS 1090 1100 1110 1120 1130 1140 DVWSYGVLLW EIFSLGGSPY PGVQMDEDFC SRLKEGMRMR TPEYATPEIY QIMLDCWHKD 1150 1160 1170 1180 1190 1200 PKERPRFAEL VEKLGDLLQA NVQQDGKDYI PLNAILTRNS SFTYSTPTFS EDLFKDGFAD 1210 1220 1230 1240 1250 1260 PHFHSGSSDD VRYVNAFKFM SLERIKTFEE LSPNSTSMFE DYQLDTSTLL GSPLLKRFTW 1270 1280 1290 1300 1310 1320 TETKPKASMK IDLRIASKSK EAGLSDLPRP SFCFSSCGHI RPVQDDESEL GKESCCSPPP 1330 DYNSVVLYSS PPA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning of murine FLT and FLT4." Finnerty H., Kelleher K., Morris G.E., Bean K., Merberg D.M., Kriz R., Morris J.C., Sookdeo H., Turner K.J., Wood C.R. Oncogene 8:2293-2298(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: BALB/c. Tissue: Neonatal brain and Placenta.
[2]	"Isolation of a gene encoding a novel receptor tyrosine kinase from differentiated embryonic stem cells." Choi K., Wall C., Hanratty R., Keller G. Oncogene 9:1261-1266(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	"Genomic organization of the flt-1 gene encoding for vascular endothelial growth factor (VEGF) receptor-1 suggests an intimate evolutionary relationship between the 7-Ig and the 5-Ig tyrosine kinase receptors." Kondo K., Hiratsuka S., Subbalakshmi E., Matsushime H., Shibuya M. Gene 208:297-305(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: C57BL/6. Tissue: Lung.
[4]	Lubec G., Kang S.U. Submitted (APR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 110-119 AND 185-191, MASS SPECTROMETRY. Strain: C57BL/6. Tissue: Brain.
[5]	"Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium." Fong G.H., Rossant J., Gertsenstein M., Breitman M.L. Nature 376:66-70(1995) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION IN BLOOD VESSEL DEVELOPMENT DURING EMBRYOGENESIS.
[6]	"Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice." Hiratsuka S., Minowa O., Kuno J., Noda T., Shibuya M. Proc. Natl. Acad. Sci. U.S.A. 95:9349-9354(1998) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION IN MACROPHAGE MIGRATION.
[7]	"Involvement of Flt-1 tyrosine kinase (vascular endothelial growth factor receptor-1) in pathological angiogenesis." Hiratsuka S., Maru Y., Okada A., Seiki M., Noda T., Shibuya M. Cancer Res. 61:1207-1213(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN ANGIOGENESIS.
[8]	"The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis." Kearney J.B., Kappas N.C., Ellerstrom C., DiPaola F.W., Bautch V.L. Blood 103:4527-4535(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[9]	"Protein phosphorylation and expression profiling by Yin-yang multidimensional liquid chromatography (Yin-yang MDLC) mass spectrometry." Dai J., Jin W.-H., Sheng Q.-H., Shieh C.-H., Wu J.-R., Zeng R. J. Proteome Res. 6:250-262(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1263, MASS SPECTROMETRY. Tissue: Liver.
[10]	"Vascular endothelial growth factor receptor-1 regulates postnatal angiogenesis through inhibition of the excessive activation of Akt." Nishi J., Minamino T., Miyauchi H., Nojima A., Tateno K., Okada S., Orimo M., Moriya J., Fong G.H., Sunagawa K., Shibuya M., Komuro I. Circ. Res. 103:261-268(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN ANGIOGENESIS.
[11]	"Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth." Muramatsu M., Yamamoto S., Osawa T., Shibuya M. Cancer Res. 70:8211-8221(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	L07297 mRNA. Translation: AAA40078.1. X78568 mRNA. Translation: CAA55311.1. D88689 mRNA. Translation: BAA24498.1.
IPI	IPI00124497.
PIR	I78875. S49010.
RefSeq	NP_034358.2. NM_010228.3.
UniGene	Mm.389712.
3D structure databases
ProteinModelPortal	P35969.
SMR	P35969. Positions 38-751, 788-1200.
ModBase	Search...
Protein-protein interaction databases
IntAct	P35969. 2 interactions.
MINT	MINT-4139959.
PTM databases
PhosphoSite	P35969.
Proteomic databases
PaxDb	P35969.
PRIDE	P35969.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000031653; ENSMUSP00000031653; ENSMUSG00000029648.
GeneID	14254.
KEGG	mmu:14254.
UCSC	uc009aoh.1. mouse.
Organism-specific databases
CTD	2321.
MGI	MGI:95558. Flt1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00660000095441.
HOGENOM	HOG000037949.
HOVERGEN	HBG053432.
InParanoid	P35969.
KO	K05096.
OrthoDB	EOG47M1X1.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
ArrayExpress	P35969.
Bgee	P35969.
CleanEx	MM_FLT1.
Genevestigator	P35969.
GermOnline	ENSMUSG00000029648. Mus musculus.
Family and domain databases
Gene3D	2.60.40.10. 7 hits.
InterPro	IPR007110. Ig-like_dom. IPR013783. Ig-like_fold. IPR013098. Ig_I-set. IPR003599. Ig_sub. IPR003598. Ig_sub2. IPR013106. Ig_V-set. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR008266. Tyr_kinase_AS. IPR020635. Tyr_kinase_cat_dom. IPR001824. Tyr_kinase_rcpt_3_CS. IPR009135. Tyr_kinase_VEGFR1_rcpt_N. IPR009134. Tyr_kinase_VEGFR_rcpt_N. [Graphical view]
Pfam	PF07679. I-set. 2 hits. PF07714. Pkinase_Tyr. 1 hit. PF07686. V-set. 1 hit. [Graphical view]
PRINTS	PR01832. VEGFRECEPTOR. PR01833. VEGFRECEPTR1.
SMART	SM00409. IG. 5 hits. SM00408. IGc2. 2 hits. 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
BindingDB	P35969.
ChEMBL	CHEMBL3516.
ChiTaRS	FLT1. mouse.
NextBio	285579.
SOURCE	Search...

Entry information

Entry name

VGFR1_MOUSE

Accession

Primary (citable) accession number: P35969
Secondary accession number(s): O55094, Q61517

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 1, 1994
Last modified:	May 1, 2013
This is version 143 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program