VEGFR-3/Flt-4，是一種受體酪氨酸激酶，主要在淋巴管內皮細胞和淋巴組織中表達，并在淋巴管生成和淋巴細胞遷移中發揮重要作用。最新的研究表明，VEGFR-3/Flt-4在惡性腫瘤的發展中發揮了重要作用，它通過調節腫瘤血管生成和淋巴管生成來促進腫瘤的生長和轉移。

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'.

1. VEGFR3 has a role in lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms PMID: 29615616
2. These results suggest functional interactions among ATX, VEGFR-2, and VEGFR-3 in the modulation of hemovascular and lymphovascular cell activation during vascular development. PMID: 30456868
3. VEGFR-3 and CAV3 expression demonstrated immunohistochemically in SMCs of the tunica media of SV grafts predicted their early restenosis in triple-vessel CAD patients. CAV2 protein expression in SMCs of ITA grafts indicated the risk of early graft failure both in double-vessel and triple-vessel CAD subjects. PMID: 29557990
4. Single nucleotide polymorphism of VEGFR3 is associated with relapse in gastroenteropancreatic neuroendocrine neoplasms. PMID: 29787601
5. VEGFR3 single nucleotide polymorphisms association with lymphedema caused by Wuchereria bancrofti. PMID: 29122006
6. The results imply a very good sensitivity of VEGFR-3 in ESCC. VEGFR-3 may be a good diagnostic biomarker for ESCC. PMID: 28447586
7. VEGFR-3 expression was associated with depth of invasion and lymph node metastasis in gastric cancer PMID: 28939099
8. The finding of rare LAMA5 variants together with FLT4 in Milroy disease suggests that these mutations may be co-responsible for these disorders and most likely interfere with the function of lymphatics. PMID: 29908552
9. Rare inherited and de novo variants in 2,871 congenital heart disease probands identified GDF1, MYH6, and FLT4 as causative genes. PMID: 28991257
10. There was a significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from pulmonary arterial hypertension patients. PMID: 28356442
11. By treating LECs with VEGF-C156S and analyzing subsequent changes in gene expression, we identified several 'immediate early' transcription factors that showed a rapid transient upregulation VEGFR-3 stimulation. these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells, and in the control of lymphangiogenesis and permeability. PMID: 27199372
12. These results indicate that VEGF-C-induced MSC osteogenesis is mediated through VEGFR2 and VEGFR3, and followed the activation of the ERK/RUNX2 signaling pathway. PMID: 28163024
13. Assessment of VEGFR-2/VEGFR-3 on tumor samples might serve as a putative prognostic factor in renal cell carcinoma cases, identifying a subset of patients that may benefit from antiangiogenic treatments targeting VEGFR receptors. PMID: 27837630
14. This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in squamous cell carcinoma (SCC)of the tongue, whereas the expression of VEGFC, VEGFR3, CCR7, and SEMA3E are nonindependent predictive factors PMID: 27666723
15. The summarizes the structure and function features of pathway-related molecules of VEGFC/D-VEGFR3/NRP2 axis, stages of various tumors and their molecular mechanisms and significances in tuthe expression changes of these molecules in different anatomic organs or histopathologic types or development lymphatic metastasis. PMID: 27527412
16. this study uncovers a unique molecular mechanism of lymphangiogenesis in which galectin-8-dependent crosstalk among VEGF-C, podoplanin and integrin pathways plays a key role. PMID: 27066737
17. Report FLT4 genetic alterations in angiosarcomas. PMID: 26735859
18. Data indicate that foretinib suppresses angiogenesis and lymphangiogenesis by blocking vascular endothelial growth factor receptors PMID: 25909285
19. Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis. PMID: 25605009
20. A Novel Missense Mutation in FLT4 Causes Autosomal Recessive Hereditary Lymphedema PMID: 26091405
21. Missense mutations in VEGFR3 confirmed Milroy disease in two unrelated patients. PMID: 25896638
22. Case Reports: novel FLT4 gene mutation in a Chinese family with Milroy disease. PMID: 26714373
23. TNFR1 has a role in mediating TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling PMID: 25229256
24. Experiments in mice and zebrafish demonstrate that changing levels of VEGFR3/Flt4 modulates aortic lumen diameter consistent with flow-dependent remodeling PMID: 25643397
25. VEGFR-3 is a new target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury by suppressing lymphatic absorption PMID: 26121315
26. the best characterized of these signaling pathways, that involving the vascular endothelial growth factor (VEGF) family members VEGF-C and VEGF-D, together with their receptors VEGFR2 and VEGFR3. PMID: 25399804
27. Although MYC is a valuable ancillary tool in distinguishing angiosarcomas from atypical vascular lesions , FLT4 immunohistochemistry may be used to screen for patients with FLT4 gene amplification PMID: 25864386
28. Expression of VEGFR-3 was highly correlated with tumor metastasis in prostate cancer patients. PMID: 24858271
29. Neuropilin-2 mediates lymphangiogenesis of colorectal carcinoma via a VEGFC/VEGFR3 independent signaling. PMID: 25543087
30. High CD31 expression associated significantly with better survival and VEGFR3 had no association with survival. Both higher tumor grade and stage were associated with a decreased survival time PMID: 25667475
31. analysis of how VEGF, VEGFR3, and PDGFRB protein expression is influenced by RAS mutations in medullary thyroid carcinoma PMID: 24754736
32. VEGFR3 lymphatic endothelium signaling involves regulation of AKT activation via VEGFR3/VEGFR2/neuropilin 1 complex, ERK via VEGFR3/R3 homodimer, as well as regulatory roles of VE-PTP. PMID: 25524775
33. increased expression in tumors of Ang-2 may individually, or in combination with VEGFR-3, predict poor prognosis of OSCC PMID: 24040410
34. VEGF-C down-regulates VEGFR-3 in lymphatic endothelial cells PMID: 25281926
35. Increase of VEGFR3 protein expression is associated with oral squamous cell carcinoma. PMID: 24085575
36. Data suggest that VEGFC (vascular endothelial growth factor C) enhances cervical cancer invasiveness via up-regulation of galectin-3 via stimulation of NFkappaB/RELA pathway; galectin-3 interacts/activates VEGFR3. PMID: 24650367
37. The expressions of VEGF-A, VEGFR2 and VEGFR3 were studied in by immunohistochemistry in 76 endometrial carcinoma specimens. VEGFR2 and VEGFR3 receptor expression were also studied by qRT-PCR in 17 tumors in comparison to normal endometrium. PMID: 24845798
38. The present findings suggest the potential role of VEGF-C in the pathogenesis and development of a pterygium through lymphangiogenesis and the VEGF-C/VEGFR-3 pathway as a novel therapeutic target for the human pterygium. PMID: 22910845
39. These findings suggest that the VEGFC/VEGFR3 pathway acts as an enhancer of ovarian cancer progression PMID: 24508126
40. A novel GC-rich element (GRE) spanning -101/-66 sufficient for VEGFR3 transcription and activated by Sp1 and Sp3, respectively, was identified. PMID: 24710631
41. Case Report: FLT4 missense mutation in Milroy disease. PMID: 25109169
42. probe F2 facilitated the identification of the target spectrum of the two inhibitors confirming many of the previously identified (off-) targets such as AURKA, FLT4-VEGFR3, IKBKE and PDGFRbeta. PMID: 24184958
43. The CXCL12-CXCR4 axis may influence the expression of VEGFR3 in urothelial bladder carcinoma and promote tumor recurrence. PMID: 24982366
44. In primary ovarian cancer tissue, VEGFR3 expression, detected with an frequency of 26%, was mostly located in the vascular wall and across the stroma. PMID: 24713547
45. VEGF-C and VEGFR-3 expression was significantly higher in luminal A subtype compared to luminal B. PMID: 24398987
46. Transwell assays revealed that VEGF-C receptor, VEGFR-3, as well as chemokine CCL21 receptor, CC chemokine receptor 7 (CCR7), were responsible for the migration of PC3 cells toward hypoxia preconditioned MSCs PMID: 23939705
47. Lymph node and lung metastases of HEC1A cells were completely suppressed by the muscle-mediated expression of sVEGFR-3. PMID: 23614535
48. unlike an anti-VEGFR-3 Mab (mF4-31C1), DC101 was not capable of eliminating either tumor lymphangiogenesis or lymphogenous metastasis (60 % reduction of lymph node metastasis by DC101 vs 95 % by mF4-31C1). PMID: 23591595
49. Data suggest that circulating VEGFR3/CD34 are biomarkers for epithelial ovarian cancer (EOC); circulating bone marrow-derived lymphatic/vascular endothelial progenitor cells are significantly increased in EOC and correlate with lymph node metastasis. PMID: 23803010
50. Binding of VEGF-C and endostatin to recombinant VEGFR-3 is competitive. PMID: 22512651

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Cell membrane; Single-pass type I membrane protein. Cytoplasm. Nucleus.; [Isoform 1]: Cell membrane; Single-pass type I membrane protein. Note=Ligand-mediated autophosphorylation leads to rapid internalization.; [Isoform 2]: Cell membrane; Single-pass type I membrane protein.; [Isoform 3]: Secreted. Cytoplasm.

Protein kinase superfamily, Tyr protein kinase family, CSF-1/PDGF receptor subfamily

Detected in endothelial cells (at protein level). Widely expressed. Detected in fetal spleen, lung and brain. Detected in adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate, heart, and kidney.

HGNC: 3767

OMIM: 136352

KEGG: hsa:2324

STRING: 9606.ENSP00000261937

UniGene: Hs.646917