In this issue, Gao and colleagues (page 169) report their interesting findings that the absence of platelet endothelial cell adhesion molecule 1 (PECAM-1) leads to enhanced susceptibility of murine endothelial cells and human T lymphocytes to apoptosis following x-ray irradiation or staurosporine treatment. Specifically, the cytoprotective effects of PECAM-1 were shown to suppress the intrinsic mitochondrial-dependent Bax-induced cytochrome c release, caspase activation, and nuclear fragmentation. The ability of PECAM-1 to deliver survival signals to suppress Bax-induced apoptosis required the outside-in signaling properties of PECAM-1, including homophilic contact binding, intact immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and, in part, recruitment and activation of the protein-tyrosine phosphatase, SHP-2. The authors propose that the formation of the PECAM-1/SHP-2 signaling complex may affect signal transduction pathways that modulate either the location and/or activation state of pre-existing pro- and antiapoptotic components of the cell-death pathway.
While the concept that homophilic engagement of PECAM-1 can result in the transduction of survival signals in vascular endothelial cells and in macrophage phagocytosis has been previously demonstrated (Noble et al, J Immunol. 1999;162:1376-1383; Brown et al, Nature. 2002;418:200-203), these workers attempt to define the complex molecular mechanisms by which PECAM-1 may exert cytoprotective effects in suppression of apoptosis. They show that PECAM-1 can negatively regulate intrinsic mitochondrial-dependent Bax-mediated apoptosis by preventing a post–Bax-translocation event, but not extrinsic Fas-mediated apoptosis. This cytoprotective effect of the PECAM-1/SHP-2 signaling pathway does not appear to involve phosphatidylinositol-3 (PI-3) kinase–serine/threonine kinase (Akt), or integrin activation. Further studies will be required to unravel the importance of PECAM-1 ITIM (inhibitory) and ITSM (switch)–signaling properties, the spatial-temporal organization of signaling complexes, and subcellular compartmentalization that lead to modulation of pre-existing signaling circuits, including the cell-death machinery.
