VGFR3_HUMAN - dbPTM
VGFR3_HUMAN - PTM Information in dbPTM
Basic Information of Protein
UniProt ID VGFR3_HUMAN
UniProt AC P35916
Protein Name Vascular endothelial growth factor receptor 3
Gene Name FLT4
Organism Homo sapiens (Human).
Sequence Length 1363
Subcellular Localization Cell membrane
Single-pass type I membrane protein. Cytoplasm . Nucleus . Ligand-mediated autophosphorylation leads to rapid internalization.
Isoform 1: Cell membrane
Single-pass type I membrane protein. Ligand-mediated autophosphorylation le
Protein Description 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'..
Protein Sequence MQRGAALCLRLWLCLGLLDGLVSGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWAWPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARIEGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDGQEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSLELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNVSQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAAYPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNVPPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQDLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKVGQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHDAHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRSHDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEEKSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSMEIVILVGTGVIAVFFWVLLLLIFCNMRRPAHADIKTGYLSIIMDPGEVPLEEQCEYLSYDASQWEFPRERLHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKILIHIGNHLNVVNLLGACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRFRAMVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLTMEDLVCYSFQVARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLKWMAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELATPAIRRIMLNCWSGDPKARPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFSQVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTFEEFPMTPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPGQNVAVTRAHPDSQGRRRRPERGARGGQVFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY
Overview of Protein Modification Sites with Functional and Structural Information
Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations Modification Substrate Peptides
&
Secondary Structure		 ASA (%) Reference Orthologous
Protein Cluster
33N-linked_GlycosylationSMTPPTLNITEESHV
CCCCCCCCCCCCEEE		41.4323878260
104N-linked_GlycosylationLLHEVHANDTGSYVC
EEEEECCCCCCCEEE		32.2823878260
166N-linked_GlycosylationLVSIPGLNVTLRSQS
EEECCCCCEEECCCC		30.55UniProtKB CARBOHYD
251N-linked_GlycosylationVGEKLVLNCTVWAEF
HCCEEEEEEEEEEEE		16.37UniProtKB CARBOHYD
299N-linked_GlycosylationSSILTIHNVSQHDLG
HHHEEECCCCHHHHH		31.14UniProtKB CARBOHYD
411N-linked_GlycosylationSAAGLRRNISLELVV
CCCCCCCCEEEEEEE		23.0523878260
436PhosphorylationASSPSIYSRHSRQAL
CCCCCCCCHHHCCEE		23.1124719451
515N-linked_GlycosylationTEFVEGKNKTVSKLV
HHHCCCCCCEEEEHH		56.9723878260
517PhosphorylationFVEGKNKTVSKLVIQ
HCCCCCCEEEEHHEE		39.1320068231
519PhosphorylationEGKNKTVSKLVIQNA
CCCCCEEEEHHEECC		26.0420068231
527N-linked_GlycosylationKLVIQNANVSAMYKC
EHHEECCCCEEEEEE		35.5116335952
529PhosphorylationVIQNANVSAMYKCVV
HEECCCCEEEEEEHH		13.7120068231
532PhosphorylationNANVSAMYKCVVSNK
CCCCEEEEEEHHCCC		10.8420068231
550PhosphorylationDERLIYFYVTTIPDG
CCEEEEEEEEECCCC		4.6624260401
594N-linked_GlycosylationHLRWYRLNLSTLHDA
CEEEEEEEHHHCCCC		23.97UniProtKB CARBOHYD
639PhosphorylationRHATLSLSIPRVAPE
CEEEEEEECCCCCCC		27.4624719451
683N-linked_GlycosylationEAPRLTQNLTDLLVN
HCHHHHCCHHHHHHC		39.41UniProtKB CARBOHYD
690N-linked_GlycosylationNLTDLLVNVSDSLEM
CHHHHHHCCCHHHHH		27.78UniProtKB CARBOHYD
734PhosphorylationADSNQKLSIQRVREE
CCCCCCEEEEEECHH		24.5824719451
758N-linked_GlycosylationCNAKGCVNSSASVAV
HCCCCCCCCCCEEEE		34.03UniProtKB CARBOHYD
830PhosphorylationPLEEQCEYLSYDASQ
CHHHHHCEECCCHHH		14.4720431062
833PhosphorylationEQCEYLSYDASQWEF
HHHCEECCCHHHCCC		16.9720431062
853PhosphorylationHLGRVLGYGAFGKVV
HHHHHCCCCHHHCEE		10.9120431062
863PhosphorylationFGKVVEASAFGIHKG
HHCEEEHHHCCCCCC		15.6022468782
871PhosphorylationAFGIHKGSSCDTVAV
HCCCCCCCCCCCHHH		32.3728258704
872PhosphorylationFGIHKGSSCDTVAVK
CCCCCCCCCCCHHHH		25.3628258704
875PhosphorylationHKGSSCDTVAVKMLK
CCCCCCCCHHHHHHH		18.0722468782
886PhosphorylationKMLKEGATASEHRAL
HHHHCCCCHHHHHHH		41.39-
953PhosphorylationFSPCAEKSPEQRGRF
CCCCCCCCHHHHHHH		25.7723403867
976PhosphorylationLDRRRPGSSDRVLFA
HHCCCCCCCCCEEEE		31.57-
986PhosphorylationRVLFARFSKTEGGAR
CEEEEEEECCCCCCC		32.87-
1063PhosphorylationFGLARDIYKDPDYVR
CCCCCHHHCCCCHHC		17.3910102632
1064UbiquitinationGLARDIYKDPDYVRK
CCCCHHHCCCCHHCC		64.2229967540
1068PhosphorylationDIYKDPDYVRKGSAR
HHHCCCCHHCCCCCC		13.9328152594
1079UbiquitinationGSARLPLKWMAPESI
CCCCCCCCCCCCHHH		32.74-
1163PhosphorylationPKARPAFSELVEILG
CCCCHHHHHHHHHHH		31.93-
1217PhosphorylationAQADAEDSPPSLQRH
HHHCCCCCCCCHHHH		30.1627422710
1220PhosphorylationDAEDSPPSLQRHSLA
CCCCCCCCHHHHHHH		40.2826091039
1230PhosphorylationRHSLAARYYNWVSFP
HHHHHHHHCCCCCCC		9.0912881528
1231PhosphorylationHSLAARYYNWVSFPG
HHHHHHHCCCCCCCC		9.3012881528
1235PhosphorylationARYYNWVSFPGCLAR
HHHCCCCCCCCHHHC		19.8228857561
1253UbiquitinationTRGSSRMKTFEEFPM
CCCCCCCCCCCCCCC		49.29-
1254PhosphorylationRGSSRMKTFEEFPMT
CCCCCCCCCCCCCCC		27.2523663014
1261PhosphorylationTFEEFPMTPTTYKGS
CCCCCCCCCCCEECC		20.0923663014
1263PhosphorylationEEFPMTPTTYKGSVD
CCCCCCCCCEECCCC		33.3223663014
1264PhosphorylationEFPMTPTTYKGSVDN
CCCCCCCCEECCCCC		25.1723663014
1265PhosphorylationFPMTPTTYKGSVDNQ
CCCCCCCEECCCCCC		18.8123663014
1266UbiquitinationPMTPTTYKGSVDNQT
CCCCCCEECCCCCCC		42.49-
1295PhosphorylationESRHRQESGFSCKGP
HHHHHHHCCCCCCCC		36.4824719451
1300UbiquitinationQESGFSCKGPGQNVA
HHCCCCCCCCCCCEE		67.93-
1309PhosphorylationPGQNVAVTRAHPDSQ
CCCCEEEEECCCCCC		16.6424719451
1333PhosphorylationARGGQVFYNSEYGEL
CCCCCEEECCCCCCC		20.9412881528
1337PhosphorylationQVFYNSEYGELSEPS
CEEECCCCCCCCCCC		18.7412881528
1362PhosphorylationVTFFTDNSY------
EEEEECCCC------		34.7228857561
1363PhosphorylationTFFTDNSY-------
EEEECCCC-------		28.911327515
Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)
Modified Location Modified Residue Modification Type of Upstream Proteins Gene Name of Upstream Proteins UniProt AC of Upstream Proteins Sources
830YPhosphorylationKinaseSRCP12931
Uniprot
833YPhosphorylationKinaseSRCP12931
Uniprot
853YPhosphorylationKinaseSRCP12931
Uniprot
1063YPhosphorylationKinaseSRCP12931
Uniprot
1063YPhosphorylationKinaseFLT4P35916
GPS
1068YPhosphorylationKinaseFLT4P35916
GPS
1230YPhosphorylationKinaseFLT4P35916
GPS
1230YPhosphorylationKinaseKDRP35968
GPS
1231YPhosphorylationKinaseKDRP35968
GPS
1231YPhosphorylationKinaseFLT4P35916
GPS
1265YPhosphorylationKinaseFLT4P35916
GPS
1265YPhosphorylationKinaseKDRP35968
GPS
1333YPhosphorylationKinaseFLT4P35916
GPS
1333YPhosphorylationKinaseSRCP12931
Uniprot
1337YPhosphorylationKinaseSRCP12931
Uniprot
1337YPhosphorylationKinaseFLT4P35916
GPS
1363YPhosphorylationKinaseFLT4P35916
GPS
Functions of PTM Sites
Modified Location Modified Residue Modification Function Reference

Oops, there are no descriptions of PTM sites of VGFR3_HUMAN !!
Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location Modification Variant Position
(Distance <= 10) 		Residue Change SAP Related Disease Reference

Oops, there are no SNP-PTM records of VGFR3_HUMAN !!
Protein-Protein Interaction
Interacting Protein Gene Name Interaction Type PPI Reference Domain-Domain Interactions
VEGFC_HUMANVEGFCphysical
8700872
SHC1_HUMANSHC1physical
7970715
GRB2_HUMANGRB2physical
7970715
ITB1_HUMANITGB1physical
11553610
SHC1_HUMANSHC1physical
8662748
VEGFD_HUMANFIGFphysical
11279005
VEGFD_MOUSEFigfphysical
11279005
VEGFD_MOUSEFigfphysical
11574540
DUS19_HUMANDUSP19physical
28065597
Drug and Disease Associations
Kegg Disease
H00535 Lymphedemas, including: Lymphedema, hereditary I; Lymphedema-distichiasis syndrome (LD); Hypotrichos
OMIM Disease
153100Lymphedema, hereditary, 1A (LMPH1A)
602089Hemangioma, capillary infantile (HCI)
Kegg Drug
D03218 Axitinib (JAN/USAN); Inlyta (TN)
D05380 Pazopanib hydrochloride (JAN/USAN); Votrient (TN)
D06272 Sorafenib tosilate (JAN); Sorafenib tosylate (USAN); Nexavar (TN)
D06285 Vatalanib (USAN/INN)
D06402 Sunitinib malate (JAN/USAN); Sutent (TN)
D06678 Motesanib; AMG 706
D08503 Toceranib (USAN)
D08524 Sorafenib (USAN/INN)
D08544 Toceranib phosphate (USAN)
D08552 Sunitinib (INN)
D08881 Cediranib (USAN/INN)
D08883 Cediranib maleate (JAN/USAN)
D08907 Dovitinib lactate (USAN)
D08947 Motesanib phosphate (JAN); Motesanib diphosphate (USAN)
D09635 Linifanib (USAN/INN)
D09683 Tivozanib (USAN/INN)
D10062 Cabozantinib (USAN)
D10095 Cabozantinib s-malate (USAN); Cometriq (TN)
D10137 Regorafenib hydrate (JAN); Stivarga (TN)
D10138 Regorafenib (USAN/INN)
D10190 Tivozanib hydrochloride (USAN); Tivozanib hydrochloride monohydrate
D10396 Nintedanib esylate (USAN)
DrugBank
There are no disease associations of PTM sites.
Regulatory Network of VGFR3_HUMAN

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Related Literatures of Post-Translational Modification
N-linked Glycosylation
ReferencePubMed
"Human plasma N-glycoproteome analysis by immunoaffinity subtraction,hydrazide chemistry, and mass spectrometry.";
Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,Moore R.J., Smith R.D.;
J. Proteome Res. 4:2070-2080(2005).
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-527, AND MASSSPECTROMETRY.
Phosphorylation
ReferencePubMed
"Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of thereceptor intrinsic kinase activity.";
Galvagni F., Pennacchini S., Salameh A., Rocchigiani M., Neri F.,Orlandini M., Petraglia F., Gotta S., Sardone G.L., Matteucci G.,Terstappen G.C., Oliviero S.;
Circ. Res. 106:1839-1848(2010).
Cited for: PHOSPHORYLATION AT TYR-830; TYR-833; TYR-853; TYR-1063; TYR-1068;TYR-1333 AND TYR-1337, IDENTIFICATION IN A COMPLEX WITH SRC AND ITGB1,MUTAGENESIS OF TYR-1063; TYR-1068 AND TYR-1337, ENZYME REGULATION BYMAZ51, INTERACTION WITH ITGB1; CRK AND SHC1, FUNCTION IN ACTIVATION OFMAPK8 AND IN REGULATION OF ANGIOGENIC SPROUTING, AND MASSSPECTROMETRY.
"Global survey of phosphotyrosine signaling identifies oncogenickinases in lung cancer.";
Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J.,Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L.,Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J.,Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X.,Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.;
Cell 131:1190-1203(2007).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1063 AND TYR-1068, ANDMASS SPECTROMETRY.
"Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation,migration, and survival of endothelial cells through the activation ofERK, AKT, and JNK pathways.";
Salameh A., Galvagni F., Bardelli M., Bussolino F., Oliviero S.;
Blood 106:3423-3431(2005).
Cited for: FUNCTION IN ACTIVATION OF AKT1; MAPK1/ERK2; MAPK3/ERK1 AND MAPK8,FUNCTION IN PROMOTING CELL SURVIVAL; PROLIFERATION AND MIGRATION,CHARACTERIZATION OF ISOFORM 1 AND ISOFORM 2, INTERACTION WITH CRK ANDGRB2, PHOSPHORYLATION AT TYR-1063; TYR-1068; TYR-1230; TYR-1231 ANDTYR-1337, AND MUTAGENESIS OF TYR-1063; TYR-1068; TYR-1230 ANDTYR-1231.
"Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelialcells regulates tyrosine phosphorylation sites.";
Dixelius J., Makinen T., Wirzenius M., Karkkainen M.J., Wernstedt C.,Alitalo K., Claesson-Welsh L.;
J. Biol. Chem. 278:40973-40979(2003).
Cited for: INTERACTION WITH KDR, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION,CHARACTERIZATION OF VARIANT LMPH1A PRO-1041, MUTAGENESIS OF LYS-879;TYR-1230; TYR-1231; TYR-1265; TYR-1333; TYR-1337 AND TYR-1363, ANDPHOSPHORYLATION AT TYR-1230; TYR-1231; TYR-1265; TYR-1333; TYR-1337AND TYR-1363.

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