4bsk

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Crystal structure of VEGF-C in complex with VEGFR-3 domains D1-2Crystal structure of VEGF-C in complex with VEGFR-3 domains D1-2

Structural highlights

4bsk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 4.201Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

VGFR3_HUMAN Milroy disease. The disease is caused by mutations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.

Function

VGFR3_HUMAN 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] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]

Publication Abstract from PubMed

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.

Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation.,Leppanen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K Proc Natl Acad Sci U S A. 2013 Jul 22. PMID:23878260[16]

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

See Also

References

  1. ↑ Lee J, Gray A, Yuan J, Luoh SM, Avraham H, Wood WI. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1988-92. PMID:8700872
  2. ↑ Fournier E, Dubreuil P, Birnbaum D, Borg JP. Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming capacity of the FLT4 receptor. Oncogene. 1995 Sep 7;11(5):921-31. PMID:7675451
  3. ↑ Achen MG, Jeltsch M, Kukk E, Makinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):548-53. PMID:9435229
  4. ↑ Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001 Sep 3;20(17):4762-73. PMID:11532940 doi:10.1093/emboj/20.17.4762
  5. ↑ Alam A, Herault JP, Barron P, Favier B, Fons P, Delesque-Touchard N, Senegas I, Laboudie P, Bonnin J, Cassan C, Savi P, Ruggeri B, Carmeliet P, Bono F, Herbert JM. Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity. Biochem Biophys Res Commun. 2004 Nov 12;324(2):909-15. PMID:15474514 doi:10.1016/j.bbrc.2004.08.237
  6. ↑ Wang JF, Zhang X, Groopman JE. Activation of vascular endothelial growth factor receptor-3 and its downstream signaling promote cell survival under oxidative stress. J Biol Chem. 2004 Jun 25;279(26):27088-97. Epub 2004 Apr 21. PMID:15102829 doi:10.1074/jbc.M314015200
  7. ↑ Salameh A, Galvagni F, Bardelli M, Bussolino F, Oliviero S. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood. 2005 Nov 15;106(10):3423-31. Epub 2005 Aug 2. PMID:16076871 doi:10.1182/blood-2005-04-1388
  8. ↑ Garces CA, Kurenova EV, Golubovskaya VM, Cance WG. Vascular endothelial growth factor receptor-3 and focal adhesion kinase bind and suppress apoptosis in breast cancer cells. Cancer Res. 2006 Feb 1;66(3):1446-54. PMID:16452200 doi:10.1158/0008-5472.CAN-05-1661
  9. ↑ Goldman J, Rutkowski JM, Shields JD, Pasquier MC, Cui Y, Schmokel HG, Willey S, Hicklin DJ, Pytowski B, Swartz MA. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J. 2007 Apr;21(4):1003-12. Epub 2007 Jan 8. PMID:17210781 doi:10.1096/fj.06-6656com
  10. ↑ Matsuura M, Onimaru M, Yonemitsu Y, Suzuki H, Nakano T, Ishibashi H, Shirasuna K, Sueishi K. Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells. Am J Pathol. 2009 Oct;175(4):1709-21. doi: 10.2353/ajpath.2009.081139. Epub 2009 , Sep 24. PMID:19779139 doi:10.2353/ajpath.2009.081139
  11. ↑ Kurenova EV, Hunt DL, He D, Magis AT, Ostrov DA, Cance WG. Small molecule chloropyramine hydrochloride (C4) targets the binding site of focal adhesion kinase and vascular endothelial growth factor receptor 3 and suppresses breast cancer growth in vivo. J Med Chem. 2009 Aug 13;52(15):4716-24. doi: 10.1021/jm900159g. PMID:19610651 doi:10.1021/jm900159g
  12. ↑ Galvagni F, Pennacchini S, Salameh A, Rocchigiani M, Neri F, Orlandini M, Petraglia F, Gotta S, Sardone GL, Matteucci G, Terstappen GC, Oliviero S. Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity. Circ Res. 2010 Jun 25;106(12):1839-48. doi: 10.1161/CIRCRESAHA.109.206326. Epub, 2010 Apr 29. PMID:20431062 doi:10.1161/CIRCRESAHA.109.206326
  13. ↑ Nilsson I, Bahram F, Li X, Gualandi L, Koch S, Jarvius M, Soderberg O, Anisimov A, Kholova I, Pytowski B, Baldwin M, Yla-Herttuala S, Alitalo K, Kreuger J, Claesson-Welsh L. VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J. 2010 Apr 21;29(8):1377-88. doi: 10.1038/emboj.2010.30. Epub 2010 Mar 11. PMID:20224550 doi:10.1038/emboj.2010.30
  14. ↑ Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature. 2010 May 27;465(7297):483-6. doi: 10.1038/nature09002. PMID:20445537 doi:10.1038/nature09002
  15. ↑ Yuen D, Pytowski B, Chen L. Combined blockade of VEGFR-2 and VEGFR-3 inhibits inflammatory lymphangiogenesis in early and middle stages. Invest Ophthalmol Vis Sci. 2011 Apr 20;52(5):2593-7. doi: 10.1167/iovs.10-6408. PMID:21273538 doi:10.1167/iovs.10-6408
  16. ↑ Leppanen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Natl Acad Sci U S A. 2013 Jul 22. PMID:23878260 doi:10.1073/pnas.1301415110

4bsk, resolution 4.20Å

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