FLT4 (fms related receptor tyrosine kinase 4)

Gene

• Entrez ID: 2324
• Gene name: Fms related receptor tyrosine kinase 4
• Gene symbol: FLT4
• Synonyms: CHTD7, FLT-4, FLT41, LMPH1A, LMPHM1, PCL, VEGFR-3, VEGFR3
• Chromosome: 5
• Chromosome location: 5q35.3
• Summary: This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involved in lymphangiogenesis and maintenance of the lymphatic endothelium. Mutations in this gene cause hereditary lymphedema type

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs34255532	G>A,C	Pathogenic, uncertain-significance, benign	Non coding transcript variant, coding sequence variant, missense variant
rs121909650	C>G	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909651	A>G	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909652	G>A	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909653	T>C	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909654	C>T	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909655	A>G	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909656	C>T	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs121909657	C>T	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs267606818	C>T	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs587776833	AGA>-	Pathogenic	Non coding transcript variant, inframe deletion, coding sequence variant
rs755445139	G>-,GG	Pathogenic	Frameshift variant, non coding transcript variant, upstream transcript variant, coding sequence variant, genic upstream transcript variant
rs1451816005	G>A	Likely-pathogenic	Coding sequence variant, missense variant, non coding transcript variant
rs1554109707	C>G,T	Likely-pathogenic	Coding sequence variant, non coding transcript variant, missense variant
rs1554115894	A>G	Drug-response	Coding sequence variant, 5 prime UTR variant, non coding transcript variant, missense variant
rs1581616817	G>A	Pathogenic	Stop gained, coding sequence variant, non coding transcript variant
rs1581655293	->C	Pathogenic	Coding sequence variant, non coding transcript variant, frameshift variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT043539	hsa-miR-331-3p	CLASH	23622248
MIRT053184	hsa-miR-1236-3p	Luciferase reporter assay, pSILAC, qRT-PCR, Western blot	22223733
MIRT053184	hsa-miR-1236-3p	Luciferase reporter assay, pSILAC, qRT-PCR, Western blot	22223733
MIRT999075	hsa-miR-1184	CLIP-seq
MIRT999076	hsa-miR-1205	CLIP-seq
MIRT999077	hsa-miR-1266	CLIP-seq
MIRT999078	hsa-miR-1293	CLIP-seq
MIRT999079	hsa-miR-2467-3p	CLIP-seq
MIRT999080	hsa-miR-3132	CLIP-seq
MIRT999081	hsa-miR-3150b-3p	CLIP-seq
MIRT999082	hsa-miR-3158-5p	CLIP-seq
MIRT999083	hsa-miR-3174	CLIP-seq
MIRT999084	hsa-miR-3184	CLIP-seq
MIRT999085	hsa-miR-3664-3p	CLIP-seq
MIRT999086	hsa-miR-3678-3p	CLIP-seq
MIRT999087	hsa-miR-3925-3p	CLIP-seq
MIRT999088	hsa-miR-423-5p	CLIP-seq
MIRT999089	hsa-miR-4257	CLIP-seq
MIRT999090	hsa-miR-4483	CLIP-seq
MIRT999091	hsa-miR-4512	CLIP-seq
MIRT999092	hsa-miR-4518	CLIP-seq
MIRT999093	hsa-miR-4646-5p	CLIP-seq
MIRT999094	hsa-miR-4689	CLIP-seq
MIRT999095	hsa-miR-4716-3p	CLIP-seq
MIRT999096	hsa-miR-4723-5p	CLIP-seq
MIRT999097	hsa-miR-4728-5p	CLIP-seq
MIRT999098	hsa-miR-4731-5p	CLIP-seq
MIRT999099	hsa-miR-4747-5p	CLIP-seq
MIRT999100	hsa-miR-4755-3p	CLIP-seq
MIRT999101	hsa-miR-4783-5p	CLIP-seq
MIRT999102	hsa-miR-4784	CLIP-seq
MIRT999103	hsa-miR-486-3p	CLIP-seq
MIRT999104	hsa-miR-512-3p	CLIP-seq
MIRT999105	hsa-miR-515-5p	CLIP-seq
MIRT999106	hsa-miR-520a-5p	CLIP-seq
MIRT999107	hsa-miR-525-5p	CLIP-seq
MIRT999108	hsa-miR-665	CLIP-seq
MIRT999109	hsa-miR-766	CLIP-seq
MIRT999110	hsa-miR-921	CLIP-seq
MIRT1996052	hsa-miR-1908	CLIP-seq
MIRT1996053	hsa-miR-3180	CLIP-seq
MIRT1996054	hsa-miR-3180-3p	CLIP-seq
MIRT1996055	hsa-miR-3196	CLIP-seq
MIRT1996056	hsa-miR-4787-5p	CLIP-seq
MIRT1996057	hsa-miR-663	CLIP-seq
MIRT1996058	hsa-miR-759	CLIP-seq
MIRT999077	hsa-miR-1266	CLIP-seq
MIRT2388022	hsa-miR-1275	CLIP-seq
MIRT999084	hsa-miR-3184	CLIP-seq
MIRT999085	hsa-miR-3664-3p	CLIP-seq
MIRT999088	hsa-miR-423-5p	CLIP-seq
MIRT2388023	hsa-miR-4254	CLIP-seq
MIRT2388024	hsa-miR-4260	CLIP-seq
MIRT999092	hsa-miR-4518	CLIP-seq
MIRT2388025	hsa-miR-4665-5p	CLIP-seq
MIRT999095	hsa-miR-4716-3p	CLIP-seq
MIRT999096	hsa-miR-4723-5p	CLIP-seq
MIRT999097	hsa-miR-4728-5p	CLIP-seq
MIRT999103	hsa-miR-486-3p	CLIP-seq

Transcription factors

Transcription factor	Regulation	Reference
NFKB1	Activation	19901262
RELA	Activation	19901262

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001934	Process	Positive regulation of protein phosphorylation	IMP	11532940, 19779139
GO:0001938	Process	Positive regulation of endothelial cell proliferation	IMP	11532940
GO:0001944	Process	Vasculature development	ISS
GO:0001945	Process	Lymph vessel development	ISS
GO:0001946	Process	Lymphangiogenesis	IMP	19779139
GO:0001946	Process	Lymphangiogenesis	ISS
GO:0002040	Process	Sprouting angiogenesis	ISS
GO:0002244	Process	Hematopoietic progenitor cell differentiation	IBA	21873635
GO:0003016	Process	Respiratory system process	IEA
GO:0004714	Function	Transmembrane receptor protein tyrosine kinase activity	IBA	21873635
GO:0004714	Function	Transmembrane receptor protein tyrosine kinase activity	IMP	7898938
GO:0005021	Function	Vascular endothelial growth factor-activated receptor activity	IDA	9012504, 23878260
GO:0005021	Function	Vascular endothelial growth factor-activated receptor activity	IMP	11532940, 19779139
GO:0005515	Function	Protein binding	IPI	16530705, 20224550, 21130043, 22939624, 23878260, 27991863
GO:0005524	Function	ATP binding	IEA
GO:0005576	Component	Extracellular region	IEA
GO:0005654	Component	Nucleoplasm	IDA
GO:0005829	Component	Cytosol	IDA
GO:0005886	Component	Plasma membrane	IDA	7898938
GO:0005886	Component	Plasma membrane	TAS
GO:0005887	Component	Integral component of plasma membrane	IBA	21873635
GO:0007169	Process	Transmembrane receptor protein tyrosine kinase signaling pathway	IBA	21873635
GO:0007275	Process	Multicellular organism development	IBA	21873635
GO:0008284	Process	Positive regulation of cell population proliferation	IGI	11574540
GO:0008284	Process	Positive regulation of cell population proliferation	IMP	7675451, 19779139
GO:0010575	Process	Positive regulation of vascular endothelial growth factor production	IMP	19779139
GO:0010595	Process	Positive regulation of endothelial cell migration	IMP	11532940
GO:0018108	Process	Peptidyl-tyrosine phosphorylation	IDA	7898938
GO:0019838	Function	Growth factor binding	IPI	9435229
GO:0019903	Function	Protein phosphatase binding	IPI	20826270
GO:0033674	Process	Positive regulation of kinase activity	IBA	21873635
GO:0035924	Process	Cellular response to vascular endothelial growth factor stimulus	IDA	9435229
GO:0035924	Process	Cellular response to vascular endothelial growth factor stimulus	IMP	19779139
GO:0038084	Process	Vascular endothelial growth factor signaling pathway	IDA	23878260
GO:0042803	Function	Protein homodimerization activity	IDA	23878260
GO:0043066	Process	Negative regulation of apoptotic process	IMP	11532940
GO:0043235	Component	Receptor complex	IBA	21873635
GO:0043235	Component	Receptor complex	IDA	23382219
GO:0043410	Process	Positive regulation of MAPK cascade	IMP	19779139
GO:0046330	Process	Positive regulation of JNK cascade	IMP	16076871
GO:0046777	Process	Protein autophosphorylation	IDA	7675451, 9435229, 23878260
GO:0048010	Process	Vascular endothelial growth factor receptor signaling pathway	IDA	9012504
GO:0048010	Process	Vascular endothelial growth factor receptor signaling pathway	IGI	11574540
GO:0048010	Process	Vascular endothelial growth factor receptor signaling pathway	IMP	11532940, 19779139
GO:0048010	Process	Vascular endothelial growth factor receptor signaling pathway	TAS
GO:0048286	Process	Lung alveolus development	IEA
GO:0048514	Process	Blood vessel morphogenesis	ISS
GO:0060312	Process	Regulation of blood vessel remodeling	ISS
GO:0070374	Process	Positive regulation of ERK1 and ERK2 cascade	IMP	11532940
GO:0090037	Process	Positive regulation of protein kinase C signaling	IMP	11532940

Other IDs

• MIM: 136352
• HGNC: 3767
• e!Ensembl: ENSG00000037280

Protein

• UniProt ID: P35916
• Protein name: Vascular endothelial growth factor receptor 3 (VEGFR-3) (EC 2.7.10.1) (Fms-like tyrosine kinase 4) (FLT-4) (Tyrosine-protein kinase receptor FLT4)
• Protein function: 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. P
• PDB: 4BSJ, 4BSK
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF13927	Ig_3	231 → 314		Domain
  PF13927	Ig_3	559 → 657		Domain
  PF07679	I-set	678 → 765	Immunoglobulin I-set domain	Domain
  PF17988	VEGFR-2_TMD	770 → 804	VEGFR-2 Transmembrane domain	Domain
  PF07714	PK_Tyr_Ser-Thr	845 → 1169	Protein tyrosine and serine/threonine kinase	Domain

• Sequence:

  MQRGAALCLRLWLCLGLLDGLVSGYSMTPPTLNITEESHVIDTGDSLSISCRGQHPLEWA
  WPGAQEAPATGDKDSEDTGVVRDCEGTDARPYCKVLLLHEVHANDTGSYVCYYKYIKARI
  EGTTAASSYVFVRDFEQPFINKPDTLLVNRKDAMWVPCLVSIPGLNVTLRSQSSVLWPDG
  QEVVWDDRRGMLVSTPLLHDALYLQCETTWGDQDFLSNPFLVHITGNELYDIQLLPRKSL
  ELLVGEKLVLNCTVWAEFNSGVTFDWDYPGKQAERGKWVPERRSQQTHTELSSILTIHNV
  SQHDLGSYVCKANNGIQRFRESTEVIVHENPFISVEWLKGPILEATAGDELVKLPVKLAA
  YPPPEFQWYKDGKALSGRHSPHALVLKEVTEASTGTYTLALWNSAAGLRRNISLELVVNV
  PPQIHEKEASSPSIYSRHSRQALTCTAYGVPLPLSIQWHWRPWTPCKMFAQRSLRRRQQQ
  DLMPQCRDWRAVTTQDAVNPIESLDTWTEFVEGKNKTVSKLVIQNANVSAMYKCVVSNKV
  GQDERLIYFYVTTIPDGFTIESKPSEELLEGQPVLLSCQADSYKYEHLRWYRLNLSTLHD
  AHGNPLLLDCKNVHLFATPLAASLEEVAPGARHATLSLSIPRVAPEHEGHYVCEVQDRRS
  HDKHCHKKYLSVQALEAPRLTQNLTDLLVNVSDSLEMQCLVAGAHAPSIVWYKDERLLEE
  KSGVDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAVEGSEDKGSMEIVILV
  GTGVIAVFFWVLLLLIFCNMRRPAHADIKTGYLSIIMDPGEVPLEEQCEYLSYDASQWEF
  PRERLHLGRVLGYGAFGKVVEASAFGIHKGSSCDTVAVKMLKEGATASEHRALMSELKIL
  IHIGNHLNVVNLLGACTKPQGPLMVIVEFCKYGNLSNFLRAKRDAFSPCAEKSPEQRGRF
  RAMVELARLDRRRPGSSDRVLFARFSKTEGGARRASPDQEAEDLWLSPLTMEDLVCYSFQ
  VARGMEFLASRKCIHRDLAARNILLSESDVVKICDFGLARDIYKDPDYVRKGSARLPLKW
  MAPESIFDKVYTTQSDVWSFGVLLWEIFSLGASPYPGVQINEEFCQRLRDGTRMRAPELA
  TPAIRRIMLNCWSGDPKARPAFSELVEILGDLLQGRGLQEEEEVCMAPRSSQSSEEGSFS
  QVSTMALHIAQADAEDSPPSLQRHSLAARYYNWVSFPGCLARGAETRGSSRMKTFEEFPM
  TPTTYKGSVDNQTDSGMVLASEEFEQIESRHRQESGFSCKGPGQNVAVTRAHPDSQGRRR
  RPERGARGGQVFYNSEYGELSEPSEEDHCSPSARVTFFTDNSY

• Sequence length: 1363

Pathways

KEGG:

MAPK signaling pathway
Ras signaling pathway
Rap1 signaling pathway
Calcium signaling pathway
PI3K-Akt signaling pathway
Focal adhesion
Pathways in cancer
Breast cancer

Reactome:

VEGF binds to VEGFR leading to receptor dimerization

Associated diseases

Causal
Disease name	Disease term	dbSNP ID	References
Hemangioma	Hemangioma, HEMANGIOMA, CAPILLARY INFANTILE, Infantile hemangioma	rs119475040, rs121917766	11807987
Hydrops fetalis	Hydrops Fetalis	rs28935477, rs1131691986	16965327
Multiple congenital anomalies	Multiple congenital anomalies	rs1057517732	19002718, 24167460, 12960217, 23074044, 15689446, 9817924
Renal carcinoma	Conventional (Clear Cell) Renal Cell Carcinoma, Clear-cell metastatic renal cell carcinoma	rs121913668, rs121913670, rs121913243, rs786202724	25239121
Sarcoma	Sarcoma	rs11540652, rs104886003, rs137852790, rs1555927374
Tetralogy of fallot	Tetralogy of Fallot	rs28939668, rs727504412, rs864321649, rs774966208, rs876660981, rs886044220, rs1114167357, rs1569484126, rs1569484164, rs1569484122, rs1569484124, rs1569484042, rs1569484120, rs1569484299, rs1569484301, rs1569484288	28991257

Unknown
Disease name	Disease term	dbSNP ID	References
Capillary hemangioma	NON RARE IN EUROPE: Infantile capillary hemangioma	rs933640981
Congenital epicanthus	Congenital Epicanthus
Dysmorphic features	Dysmorphic features		24167460, 9817924, 12960217, 19002718, 23074044, 15689446
Erysipelas	Erysipelas
Hemangiosarcoma	Hemangiosarcoma	rs199469669
Hyperkeratosis	Hyperkeratosis
Hypoplasia of lymphatic vessels	Hypoplasia of lymphatic vessels
Metastatic melanoma	Metastatic melanoma
Milroy disease	Milroy Disease		16965327, 10856194, 16924388, 17458866, 15102829, 19289394, 12881528, 9817924, 10835628, 23074044, 26091405
Sclerocystic ovaries	Sclerocystic Ovaries		21411543
Polycystic ovary syndrome	Polycystic Ovary Syndrome		21411543
Skin neoplasms	Skin Neoplasms
Specific learning disorder	Specific learning disability	rs1057519497
Strawberry nevus of skin	Strawberry nevus of skin
Testicular hydrocele	Testicular Hydrocele
Vulval varices	Varicosity