Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5090
Title: 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
Authors: Salameh, A.
Galvagni, Federico 
Bardelli, M.
Bussolino, F.
S., Oliviero
Issue Date: 2005
Project: None 
Journal: BLOOD
Abstract: 
Vascular endothelial growth factor receptor-3 (VEGFR-3) plays a key role for the remodeling of the primary capillary plexus in the embryo and contributes to angiogenesis and lymphangiogenesis in the adult. However, VEGFR-3 signal transduction pathways remain to be elucidated. Here we investigated VEGFR-3 signaling in primary human umbilical vein endothelial cells (HUVECs) by the systematic mutation of the tyrosine residues potentially involved in VEGFR-3 signaling and identified the tyrosines critical for its function. Y1068 was shown 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 mitogen-activated protein kinase kinase-4 (MKK4), activates c-Jun N-terminal kinase-1/2 (JNK1/2). Inhibition of JNK1/2 function either by specific peptide inhibitor JNKI1 or by RNA interference (RNAi) demonstrated that activation of JNK1/2 is required for a VEGFR-3-dependent prosurvival signaling. Y1230/Y1231 contributes, together with Y1337, to proliferation, migration, and survival of endothelial cells. Phospho-Y1230/Y1231 directly recruits growth factor receptor-bonus protein (GRB2) to the receptor, inducing the activation of both AKT and extracellular signal-related kinase 1/2 (ERK1/2) signaling. Finally, we observed that Y1063 and Y1230/Y1231 signaling converge to induce c-JUN expression, and RNAi experiments demonstrated that c-JUN is required for growth factor-induced prosurvival signaling in primary endothelial cells.
Description: 
36280
URI: http://hdl.handle.net/20.500.12779/5090
ISSN: 0006-4971
DOI: 10.1182/blood-2005-04-1388
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