1flt

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VEGF IN COMPLEX WITH DOMAIN 2 OF THE FLT-1 RECEPTORVEGF IN COMPLEX WITH DOMAIN 2 OF THE FLT-1 RECEPTOR

Structural highlights

1flt is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Activity:Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[VEGFA_HUMAN] Defects in VEGFA are a cause of susceptibility to microvascular complications of diabetes type 1 (MVCD1) [MIM:603933]. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. [VGFR1_HUMAN] Note=Can contribute to cancer cell survival, proliferation, migration, and invasion, and tumor angiogenesis and metastasis. May contribute to cancer pathogenesis by promoting inflammatory responses and recruitment of tumor-infiltrating macrophages. Note=Abnormally high expression of soluble isoforms (isoform 2, isoform 3 or isoform 4) may be a cause of preeclampsia.

Function

[VEGFA_HUMAN] Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth.[1] [2] [3] [VGFR1_HUMAN] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell survival, cell migration, macrophage function, chemotaxis, and cancer cell invasion. May play an essential role as a negative regulator of embryonic angiogenesis by inhibiting excessive proliferation of endothelial cells. Can promote endothelial cell proliferation, survival and angiogenesis in adulthood. Its function in promoting cell proliferation seems to be cell-type specific. Promotes PGF-mediated proliferation of endothelial cells, proliferation of some types of cancer cells, but does not promote proliferation of normal fibroblasts (in vitro). Has very high affinity for VEGFA and relatively low protein kinase activity; may function as a negative regulator of VEGFA signaling by limiting the amount of free VEGFA and preventing its binding to KDR. Likewise, isoforms lacking a transmembrane domain, such as isoform 2, isoform 3 and isoform 4, may function as decoy receptors for VEGFA. Modulates KDR signaling by forming heterodimers with KDR. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leading to activation of phosphatidylinositol kinase and the downstream signaling pathway. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Phosphorylates SRC and YES1, and may also phosphorylate CBL. Isoform 1 phosphorylates PLCG. Promotes phosphorylation of AKT1 at 'Ser-473'. Promotes phosphorylation of PTK2/FAK1. Isoform 7 has a truncated kinase domain; it increases phosphorylation of SRC at 'Tyr-418' by unknown means and promotes tumor cell invasion.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Vascular endothelial growth factor (VEGF) is a homodimeric hormone that induces proliferation of endothelial cells through binding to the kinase domain receptor and the Fms-like tyrosine kinase receptor (Flt-1), the extracellular portions of which consist of seven immunoglobulin domains. 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. The crystal structure of the complex between VEGF and the second domain of Flt-1 shows domain 2 in a predominantly hydrophobic interaction with the "poles" of the VEGF dimer. Based on this structure and on mutational data, we present a model of VEGF bound to the first four domains of Flt-1.

Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.,Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM Cell. 1997 Nov 28;91(5):695-704. PMID:9393862[22]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Murphy JF, Fitzgerald DJ. Vascular endothelial growth factor induces cyclooxygenase-dependent proliferation of endothelial cells via the VEGF-2 receptor. FASEB J. 2001 Jul;15(9):1667-9. PMID:11427521
  2. ↑ Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, Foster R, Digby-Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res. 2004 Nov 1;64(21):7822-35. PMID:15520188 doi:10.1158/0008-5472.CAN-04-0934
  3. ↑ Dixelius J, Olsson AK, Thulin A, Lee C, Johansson I, Claesson-Welsh L. Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res. 2006 Feb 15;66(4):2089-97. PMID:16489009 doi:10.1158/0008-5472.CAN-05-2217
  4. ↑ Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10705-9. PMID:8248162
  5. ↑ Jin P, Zhang J, Sumariwalla PF, Ni I, Jorgensen B, Crawford D, Phillips S, Feldmann M, Shepard HM, Paleolog EM. Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis. Arthritis Res Ther. 2008;10(4):R73. doi: 10.1186/ar2447. Epub 2008 Jul 1. PMID:18593464 doi:10.1186/ar2447
  6. ↑ Sela S, Itin A, Natanson-Yaron S, Greenfield C, Goldman-Wohl D, Yagel S, Keshet E. A novel human-specific soluble vascular endothelial growth factor receptor 1: cell-type-specific splicing and implications to vascular endothelial growth factor homeostasis and preeclampsia. Circ Res. 2008 Jun 20;102(12):1566-74. doi: 10.1161/CIRCRESAHA.108.171504. Epub, 2008 May 30. PMID:18515749 doi:10.1161/CIRCRESAHA.108.171504
  7. ↑ Mezquita B, Mezquita J, Pau M, Mezquita C. A novel intracellular isoform of VEGFR-1 activates Src and promotes cell invasion in MDA-MB-231 breast cancer cells. J Cell Biochem. 2010 Jun 1;110(3):732-42. doi: 10.1002/jcb.22584. PMID:20512933 doi:10.1002/jcb.22584
  8. ↑ Seetharam L, Gotoh N, Maru Y, Neufeld G, Yamaguchi S, Shibuya M. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene. 1995 Jan 5;10(1):135-47. PMID:7824266
  9. ↑ Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood. 1996 Apr 15;87(8):3336-43. PMID:8605350
  10. ↑ Sawano A, Takahashi T, Yamaguchi S, Shibuya M. The phosphorylated 1169-tyrosine containing region of flt-1 kinase (VEGFR-1) is a major binding site for PLCgamma. Biochem Biophys Res Commun. 1997 Sep 18;238(2):487-91. PMID:9299537 doi:10.1006/bbrc.1997.7327
  11. ↑ Dunk C, Ahmed A. Vascular endothelial growth factor receptor-2-mediated mitogenesis is negatively regulated by vascular endothelial growth factor receptor-1 in tumor epithelial cells. Am J Pathol. 2001 Jan;158(1):265-73. PMID:11141500 doi:10.1016/S0002-9440(10)63965-X
  12. ↑ Angelucci C, Lama G, Iacopino F, Maglione D, Sica G. Effect of placenta growth factor-1 on proliferation and release of nitric oxide, cyclic AMP and cyclic GMP in human epithelial cells expressing the FLT-1 receptor. Growth Factors. 2001;19(3):193-206. PMID:11811792
  13. ↑ Huang K, Andersson C, Roomans GM, Ito N, Claesson-Welsh L. Signaling properties of VEGF receptor-1 and -2 homo- and heterodimers. Int J Biochem Cell Biol. 2001 Apr;33(4):315-24. PMID:11312102
  14. ↑ Cai J, Ahmad S, Jiang WG, Huang J, Kontos CD, Boulton M, Ahmed A. Activation of vascular endothelial growth factor receptor-1 sustains angiogenesis and Bcl-2 expression via the phosphatidylinositol 3-kinase pathway in endothelial cells. Diabetes. 2003 Dec;52(12):2959-68. PMID:14633857
  15. ↑ Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med. 2003 Jul;9(7):936-43. PMID:12796773 doi:10.1038/nm884
  16. ↑ Fan F, Wey JS, McCarty MF, Belcheva A, Liu W, Bauer TW, Somcio RJ, Wu Y, Hooper A, Hicklin DJ, Ellis LM. Expression and function of vascular endothelial growth factor receptor-1 on human colorectal cancer cells. Oncogene. 2005 Apr 14;24(16):2647-53. PMID:15735759 doi:10.1038/sj.onc.1208246
  17. ↑ Lesslie DP, Summy JM, Parikh NU, Fan F, Trevino JG, Sawyer TK, Metcalf CA, Shakespeare WC, Hicklin DJ, Ellis LM, Gallick GE. Vascular endothelial growth factor receptor-1 mediates migration of human colorectal carcinoma cells by activation of Src family kinases. Br J Cancer. 2006 Jun 5;94(11):1710-7. PMID:16685275 doi:10.1038/sj.bjc.6603143
  18. ↑ Tchaikovski V, Fellbrich G, Waltenberger J. The molecular basis of VEGFR-1 signal transduction pathways in primary human monocytes. Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):322-8. Epub 2007 Dec 13. PMID:18079407 doi:10.1161/ATVBAHA.107.158022
  19. ↑ Nishi J, Minamino T, Miyauchi H, Nojima A, Tateno K, Okada S, Orimo M, Moriya J, Fong GH, Sunagawa K, Shibuya M, Komuro I. Vascular endothelial growth factor receptor-1 regulates postnatal angiogenesis through inhibition of the excessive activation of Akt. Circ Res. 2008 Aug 1;103(3):261-8. doi: 10.1161/CIRCRESAHA.108.174128. Epub 2008 , Jun 26. PMID:18583712 doi:10.1161/CIRCRESAHA.108.174128
  20. ↑ Taylor AP, Leon E, Goldenberg DM. Placental growth factor (PlGF) enhances breast cancer cell motility by mobilising ERK1/2 phosphorylation and cytoskeletal rearrangement. Br J Cancer. 2010 Jun 29;103(1):82-9. doi: 10.1038/sj.bjc.6605746. Epub 2010 Jun , 15. PMID:20551949 doi:10.1038/sj.bjc.6605746
  21. ↑ Ahmad S, Hewett PW, Al-Ani B, Sissaoui S, Fujisawa T, Cudmore MJ, Ahmed A. Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis. Vasc Cell. 2011 Jul 13;3(1):15. doi: 10.1186/2045-824X-3-15. PMID:21752276 doi:10.1186/2045-824X-3-15
  22. ↑ Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell. 1997 Nov 28;91(5):695-704. PMID:9393862

1flt, resolution 1.70Å

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