EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis

Eph receptors and their ligands (ephrins) play an important role in axonal guidance, topographic mapping, and angiogenesis. The signaling pathways mediating these activities are starting to emerge and are highly cell- and receptor-type specific. Here we demonstrate that activated EphB1 recruits the adaptor proteins Grb2 and p52Shc and promotes p52Shc and c-Src tyrosine phosphorylation as well as MAPK/extracellular signal–regulated kinase (ERK) activation. EphB1-mediated increase of cell migration was abrogated by the MEK inhibitor PD98059 and Src inhibitor PP2. In contrast, cell adhesion, which we previously showed to be c-jun NH2-terminal kinase (JNK) dependent, was unaffected by ERK1/2 and Src inhibition. Expression of dominant-negative c-Src significantly reduced EphB1-dependent ERK1/2 activation and chemotaxis. Site-directed mutagenesis experiments demonstrate that tyrosines 600 and 778 of EphB1 are required for its interaction with c-Src and p52Shc. Furthermore, phosphorylation of p52Shc by c-Src is essential for its recruitment to EphB1 signaling complexes through its phosphotyrosine binding domain. Together these findings highlight a new aspect of EphB1 signaling, whereby the concerted action of c-Src and p52Shc activates MAPK/ERK and regulates events involved in cell motility

Régulation de la signalisation calcique dans l'apoptose induite par les lipoprotéines oxydées (implication dans l'athérosclérose)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Etude de l'effet prolifératif du péroxyde d'hydrogène produit par les monoamine oxydases rénales

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Signalisation apototique induite par les LDL oxydées Implication dans l’athérosclérose

The balance between vascular cell proliferation vs apoptosis plays a key role in vessel wall remodeling. Intimal migration and proliferation of smooth muscle cells (SMC), and secretion of extracellular matrix are involved in fibrous cap formation and plaque stability, whereas apoptosis of vascular cells may contribute to the erosion and instability of the plaque leading to its rupture and subsequent thrombus formation. LDL become atherogenic after undergoing oxidation within the vascular wall. Oxidized LDL (oxLDL) and oxidized lipids exhibit complex biological properties involved in endothelial dysfunction, SMC migration and proliferation, inflammation, and apoptosis. Oxidized LDL-induced apoptosis involves the extrinsic propapoptotic pathway (linked to Fas/Fas ligand) in lymphocytes, and the intrinsic mitochondrial apoptotic pathway, involving bcl-2 family members, cytochrome C release, and the terminal executive caspase-3 pathway, as well as the mitochondrial apoptotic factor AIF, in vascular cells. The apoptotic signaling of oxLDL is mediated in part by an intense and sustained rise of cytosolic calcium. The mechanisms regulating the balance between proliferation and apoptosis triggered by oxLDL and their role in vivo in atherosclerotic plaque progression remains to be clarified

Apoptose, stress du réticulum endoplasmique et autophagie induits par les LDL oxydées dans les cellules vasculaires (rôle protecteur des HDL et de chaperones du RE)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Oxidized LDLs trigger endoplasmic reticulum stress and autophagy: prevention by HDLs.

International audienceOxidized LDLs (oxLDLs) induce various cellular dysfunctions potentially implicated in the pathogenesis of atherosclerosis. For instance, toxic concentrations of oxLDLs trigger ER stress, autophagy and apoptosis. High-density lipoproteins (HDLs) counteract several adverse biological effects triggered by oxLDLs. Our recent study reveals that HDLs inhibit the activation of ER stress and of autophagy induced by oxLDLs