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Gene Review

FLT1  -  fms-related tyrosine kinase 1

Homo sapiens

Synonyms: FLT, FLT-1, FRT, Fms-like tyrosine kinase 1, Tyrosine-protein kinase FRT, ...
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Disease relevance of FLT1

  • Bovine aortic endothelial (ABAE) cells and WM35 melanoma cells were found to express KDR, while FLT1 was primarily expressed on SK-MEL-37 [1].
  • Inhibition of VEGF receptor Flk1 did not affect arthritis or atherosclerosis, indicating that inhibition of Flk1-driven angiogenesis alone was not sufficient to halt disease progression [2].
  • Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity [3].
  • We conclude that VEGFR-1 is critical in maintaining the vasculature of the neonatal retina, and that activation of VEGFR-1 by PlGF-1 is a selective strategy for preventing oxygen-induced retinal ischemia without provoking retinal neovascularization [3].
  • The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM [4].
  • Targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer [5].
  • Elevated expression of VEGFR-1 facilitates the establishment of hematogenous metastases in gastric cancer [6].

High impact information on FLT1

  • We show that the second and third domains of Flt-1 are necessary and sufficient for binding VEGF with near-native affinity, and that domain 2 alone binds only 60-fold less tightly than wild-type [7].
  • Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene [8].
  • The anti-inflammatory effects of anti-Flt1 were attributable to reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; impaired infiltration of Flt1-expressing leukocytes in inflamed tissues; and defective activation of myeloid cells [2].
  • Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment [9].
  • PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells [9].

Chemical compound and disease context of FLT1


Biological context of FLT1

  • Recent insights have shed light onto VEGFR signal transduction and the interplay between different VEGFRs and VEGF co-receptors in development, adult physiology and disease [15].
  • At 5 days postpartum (P5), VEGFR-1 protein was colocalized with retinal vessels, whereas VEGFR-2 was detected only in the neural retina [3].
  • Finally, EGCG (3-25 microg/mL) suppressed VEGF-R1 and VEGF-R2 phosphorylation, albeit incompletely [16].
  • Decreased tumor volumes after 6.12 and DC101 treatment correlated with increased tumor apoptosis and reduced vascularization, respectively, supporting the presence of autocrine VEGFR-1- and paracrine VEGFR-2-mediated pathways in lymphomagenesis [17].
  • Up-regulation of vascular endothelial growth factor receptor Flt-1 after endothelial denudation: role of transcription factor Egr-1 [18].

Anatomical context of FLT1

  • The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells [19].
  • These data suggest that the receptor tyrosine kinases encoded by the FLT gene family may have distinct functions in the regulation of the growth/differentiation of blood vessels [19].
  • These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA [20].
  • VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation [20].
  • Herein, we have analyzed the expression of Flt-1 after mechanical denudation of primary cultures of endothelial cells, which has been considered a useful in vitro model to study endothelium responses to vascular injury [18].

Associations of FLT1 with chemical compounds


Physical interactions of FLT1

  • VRP fails to bind appreciably to the extracellular domain of Flt1 or Flk1 [26].
  • Cytofluorometric analysis revealed that VEGF effectively bound only to Flt-1-expressing cells [27].
  • Mutagenesis analysis, performed on the basis of a structural model of interaction between PlGF and the minimal binding domain of Flt-1, has led to the identification of several PlGF-1 residues involved in Flt-1 recognition [28].
  • Sck also binds to Flt-1 and their binding is dependent on the kinase activities of KDR and Flt-1 [29].
  • Tyrosine 1213 of Flt-1 is a major binding site of Nck and SHP-2 [30].

Enzymatic interactions of FLT1

  • Recombinant human VEGF phosphorylated both Flt-1 and KDR and increased proliferation of all four MM cell lines in a dose-dependent fashion [31].

Co-localisations of FLT1


Regulatory relationships of FLT1


Other interactions of FLT1


Analytical, diagnostic and therapeutic context of FLT1

  • Real-time RT-PCR identified a 60-fold induction of VEGFR-1 mRNA in retina from P3 (early vascularization) to P26 (fully vascularized), and no significant change in VEGFR-2 mRNA expression [3].
  • Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo [17].
  • VEGF165 significantly increased apoptotic resistance of CLL B cells, and immunoblotting revealed that VEGF-R1 and VEGF-R2 are spontaneously phosphorylated on CLL B cells [16].
  • In this study, we examined whether Flt-1+ could be a positive signal transducer under certain pathological conditions, such as angiogenesis with tumors overexpressing a Flt-1-specific, VEGF-related ligand [10].
  • Deposition of VEGF and VEGFR was determined by immunohistochemistry [43].


  1. VEGF receptor subtypes KDR and FLT1 show different sensitivities to heparin and placenta growth factor. Terman, B., Khandke, L., Dougher-Vermazan, M., Maglione, D., Lassam, N.J., Gospodarowicz, D., Persico, M.G., Böhlen, P., Eisinger, M. Growth Factors (1994) [Pubmed]
  2. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Luttun, A., Tjwa, M., Moons, L., Wu, Y., Angelillo-Scherrer, A., Liao, F., Nagy, J.A., Hooper, A., Priller, J., De Klerck, B., Compernolle, V., Daci, E., Bohlen, P., Dewerchin, M., Herbert, J.M., Fava, R., Matthys, P., Carmeliet, G., Collen, D., Dvorak, H.F., Hicklin, D.J., Carmeliet, P. Nat. Med. (2002) [Pubmed]
  3. Selective stimulation of VEGFR-1 prevents oxygen-induced retinal vascular degeneration in retinopathy of prematurity. Shih, S.C., Ju, M., Liu, N., Smith, L.E. J. Clin. Invest. (2003) [Pubmed]
  4. GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment. Podar, K., Catley, L.P., Tai, Y.T., Shringarpure, R., Carvalho, P., Hayashi, T., Burger, R., Schlossman, R.L., Richardson, P.G., Pandite, L.N., Kumar, R., Hideshima, T., Chauhan, D., Anderson, K.C. Blood (2004) [Pubmed]
  5. Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. Abdelrahim, M., Baker, C.H., Abbruzzese, J.L., Sheikh-Hamad, D., Liu, S., Cho, S.D., Yoon, K., Safe, S. Cancer Res. (2007) [Pubmed]
  6. Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1. Mimori, K., Fukagawa, T., Kosaka, Y., Kita, Y., Ishikawa, K., Etoh, T., Iinuma, H., Sasako, M., Mori, M. Clin. Cancer Res. (2008) [Pubmed]
  7. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Wiesmann, C., Fuh, G., Christinger, H.W., Eigenbrot, C., Wells, J.A., de Vos, A.M. Cell (1997) [Pubmed]
  8. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Gerber, H.P., Malik, A.K., Solar, G.P., Sherman, D., Liang, X.H., Meng, G., Hong, K., Marsters, J.C., Ferrara, N. Nature (2002) [Pubmed]
  9. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Hattori, K., Heissig, B., Wu, Y., Dias, S., Tejada, R., Ferris, B., Hicklin, D.J., Zhu, Z., Bohlen, P., Witte, L., Hendrikx, J., Hackett, N.R., Crystal, R.G., Moore, M.A., Werb, Z., Lyden, D., Rafii, S. Nat. Med. (2002) [Pubmed]
  10. 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. (2001) [Pubmed]
  11. Inhibition of solid tumor growth by gene transfer of VEGF receptor-1 mutants. Heidenreich, R., Machein, M., Nicolaus, A., Hilbig, A., Wild, C., Clauss, M., Plate, K.H., Breier, G. Int. J. Cancer (2004) [Pubmed]
  12. Hypoxia down-regulates placenta growth factor, whereas fetal growth restriction up-regulates placenta growth factor expression: molecular evidence for "placental hyperoxia" in intrauterine growth restriction. Khaliq, A., Dunk, C., Jiang, J., Shams, M., Li, X.F., Acevedo, C., Weich, H., Whittle, M., Ahmed, A. Lab. Invest. (1999) [Pubmed]
  13. Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells. Xu, Q., Ohara, N., Chen, W., Liu, J., Sasaki, H., Morikawa, A., Sitruk-Ware, R., Johansson, E.D., Maruo, T. Hum. Reprod. (2006) [Pubmed]
  14. Bacterial wall products induce downregulation of vascular endothelial growth factor receptors on endothelial cells via a CD14-dependent mechanism: implications for surgical wound healing. Power, C., Wang, J.H., Sookhai, S., Street, J.T., Redmond, H.P. J. Surg. Res. (2001) [Pubmed]
  15. 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]
  16. VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. Lee, Y.K., Bone, N.D., Strege, A.K., Shanafelt, T.D., Jelinek, D.F., Kay, N.E. Blood (2004) [Pubmed]
  17. Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo. Wang, E.S., Teruya-Feldstein, J., Wu, Y., Zhu, Z., Hicklin, D.J., Moore, M.A. Blood (2004) [Pubmed]
  18. Up-regulation of vascular endothelial growth factor receptor Flt-1 after endothelial denudation: role of transcription factor Egr-1. Vidal, F., Aragonés, J., Alfranca, A., de Landázuri, M.O. Blood (2000) [Pubmed]
  19. 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]
  20. Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages. Murakami, M., Iwai, S., Hiratsuka, S., Yamauchi, M., Nakamura, K., Iwakura, Y., Shibuya, M. Blood (2006) [Pubmed]
  21. Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells. Barleon, B., Siemeister, G., Martiny-Baron, G., Weindel, K., Herzog, C., Marmé, D. Cancer Res. (1997) [Pubmed]
  22. Cellular expression and hormonal regulation of neuropilin-1 and -2 messenger ribonucleic Acid in the human and rhesus macaque endometrium. Germeyer, A., Hamilton, A.E., Laughlin, L.S., Lasley, B.L., Brenner, R.M., Giudice, L.C., Nayak, N.R. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  23. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. Bold, G., Altmann, K.H., Frei, J., Lang, M., Manley, P.W., Traxler, P., Wietfeld, B., Brüggen, J., Buchdunger, E., Cozens, R., Ferrari, S., Furet, P., Hofmann, F., Martiny-Baron, G., Mestan, J., Rösel, J., Sills, M., Stover, D., Acemoglu, F., Boss, E., Emmenegger, R., Lässer, L., Masso, E., Roth, R., Schlachter, C., Vetterli, W. J. Med. Chem. (2000) [Pubmed]
  24. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Bianco, R., Rosa, R., Damiano, V., Daniele, G., Gelardi, T., Garofalo, S., Tarallo, V., De Falco, S., Melisi, D., Benelli, R., Albini, A., Ryan, A., Ciardiello, F., Tortora, G. Clin. Cancer Res. (2008) [Pubmed]
  25. Targeting vascular endothelial growth factor receptor in thyroid cancer: the intracellular and extracellular implications. Keefe, S.M., Cohen, M.A., Brose, M.S. Clin. Cancer Res. (2010) [Pubmed]
  26. 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]
  27. Vascular endothelial growth factor and cellular chemotaxis: a possible autocrine pathway in adult T-cell leukemia cell invasion. Hayashibara, T., Yamada, Y., Miyanishi, T., Mori, H., Joh, T., Maeda, T., Mori, N., Maita, T., Kamihira, S., Tomonaga, M. Clin. Cancer Res. (2001) [Pubmed]
  28. Identification of placenta growth factor determinants for binding and activation of Flt-1 receptor. Errico, M., Riccioni, T., Iyer, S., Pisano, C., Acharya, K.R., Persico, M.G., De Falco, S. J. Biol. Chem. (2004) [Pubmed]
  29. Sck interacts with KDR and Flt-1 via its SH2 domain. Igarashi, K., Shigeta, K., Isohara, T., Yamano, T., Uno, I. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  30. Tyrosine 1213 of Flt-1 is a major binding site of Nck and SHP-2. Igarashi, K., Isohara, T., Kato, T., Shigeta, K., Yamano, T., Uno, I. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  31. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. Strizzi, L., Catalano, A., Vianale, G., Orecchia, S., Casalini, A., Tassi, G., Puntoni, R., Mutti, L., Procopio, A. J. Pathol. (2001) [Pubmed]
  32. 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]
  33. Expression of VEGF and its receptors by myeloma cells. Kumar, S., Witzig, T.E., Timm, M., Haug, J., Wellik, L., Fonseca, R., Greipp, P.R., Rajkumar, S.V. Leukemia (2003) [Pubmed]
  34. The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation of Flt-1 (VEGFR-1). Kobayashi, S., Sawano, A., Nojima, Y., Shibuya, M., Maru, Y. FASEB J. (2004) [Pubmed]
  35. Role of placenta growth factor (PIGF) in human extravillous trophoblast proliferation, migration and invasiveness. Athanassiades, A., Lala, P.K. Placenta (1998) [Pubmed]
  36. 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]
  37. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Hiratsuka, S., Nakamura, K., Iwai, S., Murakami, M., Itoh, T., Kijima, H., Shipley, J.M., Senior, R.M., Shibuya, M. Cancer Cell (2002) [Pubmed]
  38. KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA. Zeng, H., Zhao, D., Mukhopadhyay, D. J. Biol. Chem. (2002) [Pubmed]
  39. Crystal structure of human vascular endothelial growth factor-B: identification of amino acids important for receptor binding. Iyer, S., Scotney, P.D., Nash, A.D., Ravi Acharya, K. J. Mol. Biol. (2006) [Pubmed]
  40. Localization of vascular endothelial growth factor (VEGF) receptors in normal and adenomatous pituitaries: detection of a non-endothelial function of VEGF in pituitary tumours. Onofri, C., Theodoropoulou, M., Losa, M., Uhl, E., Lange, M., Arzt, E., Stalla, G.K., Renner, U. J. Endocrinol. (2006) [Pubmed]
  41. Vascular endothelial growth factor and its soluble receptor, Flt-1, are not correlated to erythropoietin in diabetics with normal or reduced renal function. Lenz, T., Gauer, S., Weich, H.A., Haak, T., Bergner, R., Gossmann, J. Nephrology (Carlton, Vic.) (2005) [Pubmed]
  42. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Zhou, Y., McMaster, M., Woo, K., Janatpour, M., Perry, J., Karpanen, T., Alitalo, K., Damsky, C., Fisher, S.J. Am. J. Pathol. (2002) [Pubmed]
  43. The splice variants VEGF121 and VEGF189 of the angiogenic peptide vascular endothelial growth factor are expressed in osteoarthritic cartilage. Pufe, T., Petersen, W., Tillmann, B., Mentlein, R. Arthritis Rheum. (2001) [Pubmed]
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