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Gene Review

FLT4  -  fms-related tyrosine kinase 4

Homo sapiens

Synonyms: FLT-4, FLT41, Fms-like tyrosine kinase 4, LMPH1A, PCL, ...
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Disease relevance of FLT4


Psychiatry related information on FLT4

  • A limit for MPEG initiator esterification in lipase-catalyzed CL polymerization was observed and was explained by preferential reaction of PCL propagation over MPEG esterification at long reaction times and low MPEG concentrations [6].
  • The patients were assessed using the Posttraumatic Stress Disorder Checklist (PCL), the General Health Questionnaire-28 (GHQ-28) and the Multidimensional Health Locus of Control (MHLC) [7].
  • The questionnaire included the General Health Questionnaire (GHQ-12), the post-traumatic stress disorder checklist (PCL), 15 symptoms and an assessment of alcohol intake [8].
  • During the first 6 months post-discharge, after controlling for the presence of antisocial personality disorder or PCL score and past diagnoses of alcohol/drug abuse/dependence, the presence of a severe positive symptom significantly increased the risk of aggressive behavior [9].

High impact information on FLT4


Chemical compound and disease context of FLT4

  • Recent studies have shown that missense mutations within the VEGFR-3 tyrosine kinase domain are associated with human hereditary lymphedema, suggesting an important role for this receptor in the development of the lymphatic vasculature [14].
  • The association between the NH(2) terminus of VEGFR-3, containing the peptide identified by phage display, and the COOH terminus of FAK was detected by in vitro and in vivo binding studies [15].
  • Interestingly, phototoxicity of control liposomal BPD-MA was suppressed in the presence of serum, but PCL maintained the phototoxicity in the presence of serum following PCL-mediated PDT treatment due to the stability of PCL and the reduced detachment of encapsulated photosensitizer from liposome to serum [16].
  • Four different immobilized lipases were tested, Candida antarctica type B (CALB), Rhizomucor miehei (RML), Pseudomonas cepacia (PCL), and Penicillium roquefortii (PRL). n-Hexane and diisopropyl ether (DIPE) were examined as reaction media at three different water activities (a(w)), 0.11, 0.53, and 0.97 [17].
  • The lipase from Pseudomonas cepacia (PCL) showed the highest (S)-enantioselectivity (E > 100), and cyclohexane containing 1% (v/v) buffer was identified as the best reaction medium for maintaining high enantioselectivity as well as high reaction rate [18].

Biological context of FLT4


Anatomical context of FLT4


Associations of FLT4 with chemical compounds


Physical interactions of FLT4


Co-localisations of FLT4


Regulatory relationships of FLT4

  • Surprisingly, immunoprecipitation studies detected no VEGF-C-induced autophosphorylation of VEGF-R3 in hCIPs but did so in HMVECs [30].
  • Full-length VEGF-C and VEGF-D induced predominantly and the selective VEGFR-3 ligand VEGF-C156S exclusively lymphangiogenesis [31].
  • Using western blotting we could demonstrate that interleukin-1 beta (IL-1 beta) stimulates the expression of VEGFR-3 in chondrocytes in vitro in a dose-dependent manner [32].
  • These findings were confirmed in vitro using human LECs and anti-human antagonist mAbs (IMC-1121a and hF4-3C5): both VEGFR-2 and -3 signaling were required for migration and proliferation, but tubulogenesis in 3D cultures was unaffected by VEGFR-3 blocking and partially hindered by VEGFR-2 blocking [33].
  • The results showed that VEGF-C and VEGFR-3 were highly expressed in cytoplasm and membrane in lung cancer tissues with the positive rate being 55.4 % and 52.3 % respectively, while there was no expression in the normal lung tissues [34].

Other interactions of FLT4


Analytical, diagnostic and therapeutic context of FLT4


  1. Signal transduction in human hematopoietic cells by vascular endothelial growth factor related protein, a novel ligand for the FLT4 receptor. Wang, J.F., Ganju, R.K., Liu, Z.Y., Avraham, H., Avraham, S., Groopman, J.E. Blood (1997) [Pubmed]
  2. FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Pajusola, K., Aprelikova, O., Korhonen, J., Kaipainen, A., Pertovaara, L., Alitalo, R., Alitalo, K. Cancer Res. (1992) [Pubmed]
  3. Vascular growth factors and receptors in capillary hemangioblastomas and hemangiopericytomas. Hatva, E., Böhling, T., Jääskeläinen, J., Persico, M.G., Haltia, M., Alitalo, K. Am. J. Pathol. (1996) [Pubmed]
  4. Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus. Hughes, D.C. J. Mol. Evol. (2001) [Pubmed]
  5. Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. Fielder, W., Graeven, U., Ergün, S., Verago, S., Kilic, N., Stockschläder, M., Hossfeld, D.K. Leukemia (1997) [Pubmed]
  6. Mechanistic limitations in the synthesis of polyesters by lipase-catalyzed ring-opening polymerization. Panova, A.A., Kaplan, D.L. Biotechnol. Bioeng. (2003) [Pubmed]
  7. The relationship between posttraumatic stress disorder following spinal cord injury and locus of control. Chung, M.C., Preveza, E., Papandreou, K., Prevezas, N. Journal of affective disorders. (2006) [Pubmed]
  8. The burden of psychological symptoms in UK Armed Forces. Jones, M., Rona, R.J., Hooper, R., Wesseley, S. Occupational medicine (Oxford, England) (2006) [Pubmed]
  9. The antecedents of aggressive behavior among men with schizophrenia: a prospective investigation of patients in community treatment. Hodgins, S., Hiscoke, U.L., Freese, R. Behavioral sciences & the law. (2003) [Pubmed]
  10. Vascular growth factors and lymphangiogenesis. Jussila, L., Alitalo, K. Physiol. Rev. (2002) [Pubmed]
  11. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Karkkainen, M.J., Ferrell, R.E., Lawrence, E.C., Kimak, M.A., Levinson, K.L., McTigue, M.A., Alitalo, K., Finegold, D.N. Nat. Genet. (2000) [Pubmed]
  12. Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Chen, L., Hamrah, P., Cursiefen, C., Zhang, Q., Pytowski, B., Streilein, J.W., Dana, M.R. Nat. Med. (2004) [Pubmed]
  13. VEGF receptor signalling - in control of vascular function. Olsson, A.K., Dimberg, A., Kreuger, J., Claesson-Welsh, L. Nat. Rev. Mol. Cell Biol. (2006) [Pubmed]
  14. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Karkkainen, M.J., Petrova, T.V. Oncogene (2000) [Pubmed]
  15. Vascular endothelial growth factor receptor-3 and focal adhesion kinase bind and suppress apoptosis in breast cancer cells. Garces, C.A., Kurenova, E.V., Golubovskaya, V.M., Cance, W.G. Cancer Res. (2006) [Pubmed]
  16. Polycation liposome enhances the endocytic uptake of photosensitizer into cells in the presence of serum. Takeuchi, Y., Kurohane, K., Ichikawa, K., Yonezawa, S., Ori, H., Koishi, T., Nango, M., Oku, N. Bioconjug. Chem. (2003) [Pubmed]
  17. Lipase-catalyzed methanolysis of triricinolein in organic solvent to produce 1,2(2,3)-diricinolein. Turner, C., He, X., Nguyen, T., Lin, J.T., Wong, R.Y., Lundin, R.E., Harden, L., McKeon, T. Lipids (2003) [Pubmed]
  18. Kinetic resolution of racemic alpha-methyl-beta-propiothiolactone by lipase-catalyzed hydrolysis. Hwang, B.Y., Lee, H.B., Kim, Y.G., Kim, B.G. Biotechnol. Prog. (2000) [Pubmed]
  19. Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming capacity of the FLT4 receptor. Fournier, E., Dubreuil, P., Birnbaum, D., Borg, J.P. Oncogene (1995) [Pubmed]
  20. Role of tyrosine residues and protein interaction domains of SHC adaptor in VEGF receptor 3 signaling. Fournier, E., Blaikie, P., Rosnet, O., Margolis, B., Birnbaum, D., Borg, J.P. Oncogene (1999) [Pubmed]
  21. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. Kaipainen, A., Korhonen, J., Pajusola, K., Aprelikova, O., Persico, M.G., Terman, B.I., Alitalo, K. J. Exp. Med. (1993) [Pubmed]
  22. Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Ferrell, R.E., Levinson, K.L., Esman, J.H., Kimak, M.A., Lawrence, E.C., Barmada, M.M., Finegold, D.N. Hum. Mol. Genet. (1998) [Pubmed]
  23. Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Yano, A., Fujii, Y., Iwai, A., Kawakami, S., Kageyama, Y., Kihara, K. Clin. Cancer Res. (2006) [Pubmed]
  24. VEGF-A regulates the expression of VEGF-C in human retinal pigment epithelial cells. Zhao, B., Ma, A., Cai, J., Boulton, M. The British journal of ophthalmology. (2006) [Pubmed]
  25. Signalling properties of FLT4, a proteolytically processed receptor tyrosine kinase related to two VEGF receptors. Pajusola, K., Aprelikova, O., Pelicci, G., Weich, H., Claesson-Welsh, L., Alitalo, K. Oncogene (1994) [Pubmed]
  26. Signaling pathways induced by vascular endothelial growth factor (review). Larrivée, B., Karsan, A. Int. J. Mol. Med. (2000) [Pubmed]
  27. Vascular endothelial growth factor receptor-3 activity is modulated by its association with caveolin-1 on endothelial membrane. Galvagni, F., Anselmi, F., Salameh, A., Orlandini, M., Rocchigiani, M., Oliviero, S. Biochemistry (2007) [Pubmed]
  28. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. Kärpänen, T., Heckman, C.A., Keskitalo, S., Jeltsch, M., Ollila, H., Neufeld, G., Tamagnone, L., Alitalo, K. FASEB J. (2006) [Pubmed]
  29. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Valtola, R., Salven, P., Heikkilä, P., Taipale, J., Joensuu, H., Rehn, M., Pihlajaniemi, T., Weich, H., deWaal, R., Alitalo, K. Am. J. Pathol. (1999) [Pubmed]
  30. VEGF-C promotes survival in podocytes. Foster, R.R., Satchell, S.C., Seckley, J., Emmett, M.S., Joory, K., Xing, C.Y., Saleem, M.A., Mathieson, P.W., Bates, D.O., Harper, S.J. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  31. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Rissanen, T.T., Markkanen, J.E., Gruchala, M., Heikura, T., Puranen, A., Kettunen, M.I., Kholová, I., Kauppinen, R.A., Achen, M.G., Stacker, S.A., Alitalo, K., Ylä-Herttuala, S. Circ. Res. (2003) [Pubmed]
  32. Expression of the VEGF receptor-3 in osteoarthritic chondrocytes: stimulation by interleukin-1 beta and association with beta 1-integrins. Shakibaei, M., Schulze-Tanzil, G., Mobasheri, A., Beichler, T., Dressler, J., Schwab, W. Histochem. Cell Biol. (2003) [Pubmed]
  33. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. Goldman, J., Rutkowski, J.M., Shields, J.D., Pasquier, M.C., Cui, Y., Schmökel, H.G., Willey, S., Hicklin, D.J., Pytowski, B., Swartz, M.A. FASEB J. (2007) [Pubmed]
  34. Clinical significance of VEGF-C and VEGFR-3 expression in non-small cell lung cancer. Li, J., Hong, M., Pan, T. J. Huazhong Univ. Sci. Technol. Med. Sci. (2006) [Pubmed]
  35. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Lee, J., Gray, A., Yuan, J., Luoh, S.M., Avraham, H., Wood, W.I. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  36. Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Dias, S., Choy, M., Alitalo, K., Rafii, S. Blood (2002) [Pubmed]
  37. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. Dixelius, J., Makinen, T., Wirzenius, M., Karkkainen, M.J., Wernstedt, C., Alitalo, K., Claesson-Welsh, L. J. Biol. Chem. (2003) [Pubmed]
  38. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. Stacker, S.A., Stenvers, K., Caesar, C., Vitali, A., Domagala, T., Nice, E., Roufail, S., Simpson, R.J., Moritz, R., Karpanen, T., Alitalo, K., Achen, M.G. J. Biol. Chem. (1999) [Pubmed]
  39. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Schmidt-Erfurth, U., Schlötzer-Schrehard, U., Cursiefen, C., Michels, S., Beckendorf, A., Naumann, G.O. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  40. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Kojima, H., Shijubo, N., Yamada, G., Ichimiya, S., Abe, S., Satoh, M., Sato, N. Cancer (2005) [Pubmed]
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