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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3423-3431. Prepublished online as a Blood First Edition Paper on August 2, 2005; DOI 10.1182/blood-2005-04-1388. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: 2005-04-1388v1 106/10/3423    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Salameh, A. Articles by Oliviero, S. Search for Related Content PubMed PubMed Citation Articles by Salameh, A. Articles by Oliviero, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 5, 2005 Accepted July 26, 2005 Direct recruitment of CRK and GRB2 to VEGFR-3 induce proliferation, migration and survival of endothelial cells through the activation of ERK, AKT and JNK pathways Ahmad Salameh, Federico Galvagni, Monia Bardelli, Federico Bussolino, and Salvatore Oliviero* Dipartimento di Biologia Molecolare, Universita degli Studi di Siena, Siena, Italy Istituto per la Cura e e la Ricerca sul Cancro and Dipartimento di Scienze Oncologiche, Universita di Torino, Candiolo, Torino, Italy * Corresponding author; email: oliviero{at}unisi.it. Vascular endothelial growth factor receptor (VEGFR)-3 plays a key role for the remodeling of the primary capillary plexus in embryo, and contributes to angiogenesis and lymphangiogenesis in adult. However, VEGFR-3 signal transduction pathways remain to be elucidated. Here we investigated VEGFR-3 signaling in primary human umbilical vascular endothelial cells (HUVEC) by the systematic mutation of the tyrosine residues potentially involved in VEGFR-3 signaling and identified the tyrosines critical for its function. Y1068 showed to be essential for the kinase activity of the receptor. Y1063 signals the receptor mediated survival by recruiting CRKI/II to the activated receptor inducing a signaling cascade that, via MKK4, activates c-Jun N-terminal kinase (JNK)1/2. Inhibition of JNK1/2 function either by specific peptide inhibitor JNKI1 or by RNA interference (RNAi), demonstrated activation of JNK1/2 is required for a VEGFR-3-dependent pro-survival signaling. Y1230/1231 contributes, together with Y1337, to proliferation, migration, and survival of endothelial cells. Phospho-Y1230/1231 directly recruits GRB2 to the receptor inducing the activation of both AKT and extracellular signal-related kinases (ERK)-1/2 signaling. Finally, we observed that Y1063 and Y1230/1231 signaling converge to induce c-JUN expression and RNAi experiments demonstrated that c-JUN is required for growth factor induced pro-survival signaling in primary endothelial cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Q. Xue, J. A. Nagy, E. J. Manseau, T. L. Phung, H. F. Dvorak, and L. E. Benjamin Rapamycin Inhibition of the Akt/mTOR Pathway Blocks Select Stages of VEGF-A164-Driven Angiogenesis, in Part by Blocking S6Kinase Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1172 - 1178. [Abstract] [Full Text] [PDF] F. Breitenbuecher, B. Markova, S. Kasper, B. Carius, T. Stauder, F. D. Bohmer, K. Masson, L. Ronnstrand, C. Huber, T. Kindler, et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML Blood, April 23, 2009; 113(17): 4063 - 4073. [Abstract] [Full Text] [PDF] H.-N. Kung, M.-J. Yang, C.-F. 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