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Gene Review

KDR  -  kinase insert domain receptor

Homo sapiens

Synonyms: CD309, FLK-1, FLK1, Fetal liver kinase 1, Kinase insert domain receptor, ...
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Disease relevance of KDR

  • A phage epitope library was screened by affinity for membrane-expressed KDR or for an anti-VEGF neutralizing monoclonal antibody [1].
  • Earlier, we showed that in some leukemias, a VEGF/KDR autocrine loop is essential for cell survival, whereas here we identified the molecular correlates for such an effect [2].
  • Furthermore, a highly significant correlation was observed between Ets-1 and Flt-1 (but not KDR) expression in ECs of the glioma microvasculature [3].
  • Our prior studies show that multiple myeloma (MM) cell lines and patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor (VEGFR) Flt-1 but not Flk-1/KDR [4].
  • A significant increase was observed in flt-1 (P < 0.001), KDR (P = 0.02), and flt-4 (P = 0.01) but not VEGF-B (P = 0.82) or VEGF-C (P = 0.52) expression in clear cell compared with chromophil (papillary) carcinomas [5].

High impact information on KDR


Chemical compound and disease context of KDR


Biological context of KDR

  • When coexpressed in cells with KDR, neuropilin-1 enhances the binding of VEGF165 to KDR and VEGF165-mediated chemotaxis [7].
  • We demonstrate in 2 cell lines and 5 FLT-4(+) leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios [16].
  • In addition, although VEGF receptors were higher in tumors than normal kidney, there was a significant up-regulation of only flt-1 (P = 0.003) but not KDR (P = 0.12) or flt-4 (P = 0.09) [5].
  • We demonstrated previously that antagonistic antibodies to KDR specifically inhibited VEGF-stimulated receptor activation, cell migration, and endothelial cell mitogenesis [17].
  • Although considerable experimental evidence links KDR activation to endothelial cell mitogenesis, there is still significant uncertainty concerning the role of individual VEGF receptors for other biological effects such as vascular permeability [18].

Anatomical context of KDR

  • We have investigated the expression of Flt1 and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo) lineage [19].
  • By interfering with the VEGF-KDR interaction, the peptide K237 inhibited proliferation of cultured primary human umbilical vein endothelial cells induced by recombinant human VEGF(165) in a dose-dependent and cell type-specific manner [20].
  • Our results indicate that RPE secretes VEGF toward its basal side where its receptor KDR is located on the adjacent CC endothelium, suggesting a role of VEGF in a paracrine relation, possibly in cooperation with flt-4 and its ligand [21].
  • A functional product of the KDR gene encoding a cognate VEGF receptor was also expressed by these stromal cells [11].
  • Dorsal root ganglion (DRG) neurons expressed high levels of NP-1 mRNA and protein, much lower levels of KDR, and no detectable Flt-1 [22].

Associations of KDR with chemical compounds

  • The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells [23].
  • Like VEGF, FG-4095 and DMOG increased angiogenesis in vitro, both in 95% and 21% O2, an effect that could be blocked through either Flt-1 or KDR [24].
  • As was the case for native KDR, (125)I-VEGF(165) binding to the mutant receptors was dependent upon cell surface heparan sulfate proteoglycans, and (125)I-VEGF(121) bound with an affinity equal to that of (125)I-VEGF(165) to the native and mutant receptors [25].
  • Furthermore, the mutation of tyrosine 1059 to phenylanaline results in the complete loss of KDR/EGDR-mediated intracellular Ca(2+) mobilization and MAPK phosphorylation, but the mutation of tyrosine 951 to phenylanaline did not affect these events [26].
  • In conclusion, high glucose causes an uncoupling of VEGF with NO, which enhances endothelial cell proliferation via activation of the KDR-ERK1/2 pathway [27].

Physical interactions of KDR

  • Of the synthetic peptides corresponding to selected clones tested to determine their inhibitory activity, ATWLPPR completely abolished VEGF binding to cell-displayed KDR [1].
  • Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration [28].
  • Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition [29].
  • Furthermore, we also observed that dynamin-2 coimmunoprecipitates with KDR and is required for EC signaling/survival [30].
  • We demonstrated that TFII-I binds to both the Inr and to three regulatory E boxes in the human VEGFR-2 promoter [31].

Enzymatic interactions of KDR

  • With regard to gene expression, incubation with MG63-CM abolished endogenous VEGF mRNA and protein but induced a clear-cut increase in VEGFR2 mRNA expression in EC [32].
  • Wound assays reveal that IQGAP1 and phosphorylated VEGFR2 accumulate and colocalize at the leading edge in actively migrating ECs [33].
  • Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells [34].

Co-localisations of KDR


Regulatory relationships of KDR

  • CONCLUSIONS: Cholangiocytes secrete VEGF and express VEGFR-2 and VEGFR-3, all of which are amplified in BDL cholangiocytes [36].
  • All the myeloma cell lines expressed VEGFR1 and three of the cell lines expressed VEGFR2 [37].
  • On the endothelium, NRP is expressed together with KDR, a VEGF receptor tyrosine kinase [38].
  • Further, the VEGFR-2-mediated signaling transduction pathway may be involved in LPA-induced EOC invasion and migration by regulating the secretion and activation of MMP-2 and uPA [39].
  • Taken together, our data demonstrated that TNF induces transactivation between Etk and VEGFR2, and Etk directly activates PI3K-Akt angiogenic signaling independent of VEGF-induced VEGFR2-PI3K-Akt signaling pathway [40].

Other interactions of KDR


Analytical, diagnostic and therapeutic context of KDR


  1. Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. Binétruy-Tournaire, R., Demangel, C., Malavaud, B., Vassy, R., Rouyre, S., Kraemer, M., Plouët, J., Derbin, C., Perret, G., Mazié, J.C. EMBO J. (2000) [Pubmed]
  2. VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Dias, S., Shmelkov, S.V., Lam, G., Rafii, S. Blood (2002) [Pubmed]
  3. Expression of the Ets-1 transcription factor in human astrocytomas is associated with Fms-like tyrosine kinase-1 (Flt-1)/vascular endothelial growth factor receptor-1 synthesis and neoangiogenesis. Valter, M.M., Hügel, A., Huang, H.J., Cavenee, W.K., Wiestler, O.D., Pietsch, T., Wernert, N. Cancer Res. (1999) [Pubmed]
  4. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Lin, B., Podar, K., Gupta, D., Tai, Y.T., Li, S., Weller, E., Hideshima, T., Lentzsch, S., Davies, F., Li, C., Weisberg, E., Schlossman, R.L., Richardson, P.G., Griffin, J.D., Wood, J., Munshi, N.C., Anderson, K.C. Cancer Res. (2002) [Pubmed]
  5. Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia. Gunningham, S.P., Currie, M.J., Han, C., Turner, K., Scott, P.A., Robinson, B.A., Harris, A.L., Fox, S.B. Cancer Res. (2001) [Pubmed]
  6. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., Van Dorpe, J., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., Laudenbach, V., Vermylen, P., Raat, H., Acker, T., Vleminckx, V., Van Den Bosch, L., Cashman, N., Fujisawa, H., Drost, M.R., Sciot, R., Bruyninckx, F., Hicklin, D.J., Ince, C., Gressens, P., Lupu, F., Plate, K.H., Robberecht, W., Herbert, J.M., Collen, D., Carmeliet, P. Nat. Genet. (2001) [Pubmed]
  7. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Soker, S., Takashima, S., Miao, H.Q., Neufeld, G., Klagsbrun, M. Cell (1998) [Pubmed]
  8. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cheifetz, S., Weatherbee, J.A., Tsang, M.L., Anderson, J.K., Mole, J.E., Lucas, R., Massagué, J. Cell (1987) [Pubmed]
  9. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Qi, J.H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., Anand-Apte, B. Nat. Med. (2003) [Pubmed]
  10. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Basu, S., Nagy, J.A., Pal, S., Vasile, E., Eckelhoefer, I.A., Bliss, V.S., Manseau, E.J., Dasgupta, P.S., Dvorak, H.F., Mukhopadhyay, D. Nat. Med. (2001) [Pubmed]
  11. Vascular endothelial growth factor confers a growth advantage in vitro and in vivo to stromal cells cultured from neonatal hemangiomas. Berard, M., Sordello, S., Ortega, N., Carrier, J.L., Peyri, N., Wassef, M., Bertrand, N., Enjolras, O., Drouet, L., Plouet, J. Am. J. Pathol. (1997) [Pubmed]
  12. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Ranieri, G., Patruno, R., Ruggieri, E., Montemurro, S., Valerio, P., Ribatti, D. Current medicinal chemistry. (2006) [Pubmed]
  13. Vascular endothelial growth factor overexpression by soft tissue sarcoma cells: implications for tumor growth, metastasis, and chemoresistance. Zhang, L., Hannay, J.A., Liu, J., Das, P., Zhan, M., Nguyen, T., Hicklin, D.J., Yu, D., Pollock, R.E., Lev, D. Cancer Res. (2006) [Pubmed]
  14. A randomized Phase II trial of the antiangiogenic agent SU5416 in hormone-refractory prostate cancer. Stadler, W.M., Cao, D., Vogelzang, N.J., Ryan, C.W., Hoving, K., Wright, R., Karrison, T., Vokes, E.E. Clin. Cancer Res. (2004) [Pubmed]
  15. Pituitary Tumor Transforming Gene (PTTG) Stimulates Thyroid Cell Proliferation via a Vascular Endothelial Growth Factor/Kinase Insert Domain Receptor/Inhibitor of DNA Binding-3 Autocrine Pathway. Kim, D.S., Franklyn, J.A., Boelaert, K., Eggo, M.C., Watkinson, J.C., McCabe, C.J. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  16. 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]
  17. Complete inhibition of vascular endothelial growth factor (VEGF) activities with a bifunctional diabody directed against both VEGF kinase receptors, fms-like tyrosine kinase receptor and kinase insert domain-containing receptor. Lu, D., Jimenez, X., Zhang, H., Wu, Y., Bohlen, P., Witte, L., Zhu, Z. Cancer Res. (2001) [Pubmed]
  18. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. Gille, H., Kowalski, J., Li, B., LeCouter, J., Moffat, B., Zioncheck, T.F., Pelletier, N., Ferrara, N. J. Biol. Chem. (2001) [Pubmed]
  19. Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Casella, I., Feccia, T., Chelucci, C., Samoggia, P., Castelli, G., Guerriero, R., Parolini, I., Petrucci, E., Pelosi, E., Morsilli, O., Gabbianelli, M., Testa, U., Peschle, C. Blood (2003) [Pubmed]
  20. A novel peptide isolated from a phage display library inhibits tumor growth and metastasis by blocking the binding of vascular endothelial growth factor to its kinase domain receptor. Hetian, L., Ping, A., Shumei, S., Xiaoying, L., Luowen, H., Jian, W., Lin, M., Meisheng, L., Junshan, Y., Chengchao, S. J. Biol. Chem. (2002) [Pubmed]
  21. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Blaauwgeers, H.G., Holtkamp, G.M., Rutten, H., Witmer, A.N., Koolwijk, P., Partanen, T.A., Alitalo, K., Kroon, M.E., Kijlstra, A., van Hinsbergh, V.W., Schlingemann, R.O. Am. J. Pathol. (1999) [Pubmed]
  22. Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. Cheng, L., Jia, H., Löhr, M., Bagherzadeh, A., Holmes, D.I., Selwood, D., Zachary, I. J. Biol. Chem. (2004) [Pubmed]
  23. 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]
  24. Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung. Asikainen, T.M., Schneider, B.K., Waleh, N.S., Clyman, R.I., Ho, W.B., Flippin, L.A., Günzler, V., White, C.W. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Kinase insert domain receptor (KDR) extracellular immunoglobulin-like domains 4-7 contain structural features that block receptor dimerization and vascular endothelial growth factor-induced signaling. Tao, Q., Backer, M.V., Backer, J.M., Terman, B.I. J. Biol. Chem. (2001) [Pubmed]
  26. Tyrosine residues 951 and 1059 of vascular endothelial growth factor receptor-2 (KDR) are essential for vascular permeability factor/vascular endothelial growth factor-induced endothelium migration and proliferation, respectively. Zeng, H., Sanyal, S., Mukhopadhyay, D. J. Biol. Chem. (2001) [Pubmed]
  27. Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy. Nakagawa, T., Sato, W., Sautin, Y.Y., Glushakova, O., Croker, B., Atkinson, M.A., Tisher, C.C., Johnson, R.J. J. Am. Soc. Nephrol. (2006) [Pubmed]
  28. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Favier, B., Alam, A., Barron, P., Bonnin, J., Laboudie, P., Fons, P., Mandron, M., Herault, J.P., Neufeld, G., Savi, P., Herbert, J.M., Bono, F. Blood (2006) [Pubmed]
  29. Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition. Marwick, J.A., Stevenson, C.S., Giddings, J., Macnee, W., Butler, K., Rahman, I., Kirkham, P.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2006) [Pubmed]
  30. Regulatory role of dynamin-2 in VEGFR-2/KDR-mediated endothelial signaling. Bhattacharya, R., Kang-Decker, N., Hughes, D.A., Mukherjee, P., Shah, V., McNiven, M.A., Mukhopadhyay, D. FASEB J. (2005) [Pubmed]
  31. Vascular endothelial growth factor receptor-2: counter-regulation by the transcription factors, TFII-I and TFII-IRD1. Jackson, T.A., Taylor, H.E., Sharma, D., Desiderio, S., Danoff, S.K. J. Biol. Chem. (2005) [Pubmed]
  32. Tumor-induced endothelial cell activation: role of vascular endothelial growth factor. Castilla, M.A., Neria, F., Renedo, G., Pereira, D.S., González-Pacheco, F.R., Jiménez, S., Tramón, P., Deudero, J.J., Arroyo, M.V., Yagüe, S., Caramelo, C. Am. J. Physiol., Cell Physiol. (2004) [Pubmed]
  33. IQGAP1, a novel vascular endothelial growth factor receptor binding protein, is involved in reactive oxygen species--dependent endothelial migration and proliferation. Yamaoka-Tojo, M., Ushio-Fukai, M., Hilenski, L., Dikalov, S.I., Chen, Y.E., Tojo, T., Fukai, T., Fujimoto, M., Patrushev, N.A., Wang, N., Kontos, C.D., Bloom, G.S., Alexander, R.W. Circ. Res. (2004) [Pubmed]
  34. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. Stallone, G., Schena, A., Infante, B., Di Paolo, S., Loverre, A., Maggio, G., Ranieri, E., Gesualdo, L., Schena, F.P., Grandaliano, G. N. Engl. J. Med. (2005) [Pubmed]
  35. Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration. Rissanen, T.T., Vajanto, I., Hiltunen, M.O., Rutanen, J., Kettunen, M.I., Niemi, M., Leppänen, P., Turunen, M.P., Markkanen, J.E., Arve, K., Alhava, E., Kauppinen, R.A., Ylä-Herttuala, S. Am. J. Pathol. (2002) [Pubmed]
  36. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gaudio, E., Barbaro, B., Alvaro, D., Glaser, S., Francis, H., Ueno, Y., Meininger, C.J., Franchitto, A., Onori, P., Marzioni, M., Taffetani, S., Fava, G., Stoica, G., Venter, J., Reichenbach, R., De Morrow, S., Summers, R., Alpini, G. Gastroenterology (2006) [Pubmed]
  37. 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]
  38. Neuropilin in the midst of cell migration and retraction. Soker, S. Int. J. Biochem. Cell Biol. (2001) [Pubmed]
  39. LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2). So, J., Wang, F.Q., Navari, J., Schreher, J., Fishman, D.A. Gynecol. Oncol. (2005) [Pubmed]
  40. Etk/Bmx transactivates vascular endothelial growth factor 2 and recruits phosphatidylinositol 3-kinase to mediate the tumor necrosis factor-induced angiogenic pathway. Zhang, R., Xu, Y., Ekman, N., Wu, Z., Wu, J., Alitalo, K., Min, W. J. Biol. Chem. (2003) [Pubmed]
  41. 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]
  42. Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-alpha in cultured human vascular endothelial cells. Patterson, C., Perrella, M.A., Endege, W.O., Yoshizumi, M., Lee, M.E., Haber, E. J. Clin. Invest. (1996) [Pubmed]
  43. Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Wise, L.M., Veikkola, T., Mercer, A.A., Savory, L.J., Fleming, S.B., Caesar, C., Vitali, A., Makinen, T., Alitalo, K., Stacker, S.A. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  44. 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]
  45. Increased VEGFR2 expression during human late endothelial progenitor cells expansion enhances in vitro angiogenesis with up-regulation of integrin alpha(6). Smadja, D.M., Bièche, I., Helley, D., Laurendeau, I., Simonin, G., Muller, L., Aiach, M., Gaussem, P. J. Cell. Mol. Med. (2007) [Pubmed]
  46. 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]
  47. Utilization of distinct signaling pathways by receptors for vascular endothelial cell growth factor and other mitogens in the induction of endothelial cell proliferation. Wu, L.W., Mayo, L.D., Dunbar, J.D., Kessler, K.M., Baerwald, M.R., Jaffe, E.A., Wang, D., Warren, R.S., Donner, D.B. J. Biol. Chem. (2000) [Pubmed]
  48. Expression and function of the vascular endothelial growth factor receptor FLT-1 in human eosinophils. Feistritzer, C., Kaneider, N.C., Sturn, D.H., Mosheimer, B.A., Kähler, C.M., Wiedermann, C.J. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  49. Selection of high affinity human neutralizing antibodies to VEGFR2 from a large antibody phage display library for antiangiogenesis therapy. Lu, D., Jimenez, X., Zhang, H., Bohlen, P., Witte, L., Zhu, Z. Int. J. Cancer (2002) [Pubmed]
  50. Novel highly efficient intrabody mediates complete inhibition of cell surface expression of the human vascular endothelial growth factor receptor-2 (VEGFR-2/KDR). Böldicke, T., Weber, H., Mueller, P.P., Barleon, B., Bernal, M. J. Immunol. Methods (2005) [Pubmed]
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