PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis

Abstract

IntroductionPlatelet endothelial cell adhesion molecule-1 (PECAM-1; also known as CD31) is a 130-kDa member of the immunoglobulin gene (Ig) superfamily expressed on the surface of circulating platelets and leukocytes and at the intercellular junctions of all continuous endothelium. 1-3 Extracellular Ig homology domain 1 possesses homophilic binding properties 4,5 and functions to mediate leukocyte transendothelial migration 6,7 and angiogenesis, 8 while the cytoplasmic domain harbors a functional 9-11 immunoreceptor tyrosine-based inhibitory motif (ITIM) that, when tyrosine phosphorylated, has been shown to recruit and activate the protein-tyrosine phosphatase, SHP-2, in a number of cellular systems, including human platelets, 12 bovine aortic vascular endothelial cells, 13 and rat basophilic leukemia cells. 14 Owing, in part, to its cytoplasmic ITIM, PECAM-1 has recently been assigned to the Ig-ITIM family of inhibitory receptors. 15 In addition to its role in vascular cell adhesion and signaling, there is growing evidence that PECAM-1 may be able to transduce signals that suppress programmed cell death. The first evidence of a role for PECAM-1 in apoptosis was provided by the studies of Noble et al, 16 who found that monocytes promoted the survival of serum-starved endothelial cells. Interestingly, when the anti-PECAM-1 monoclonal antibody (mAb), PECAM-1.3, was included in the monocyte/endothelial cell coculture, the cytoprotective role of added monocytes was lost. Because PECAM-1.3 inhibits PECAM-1 homophilic interactions, 4,17 the authors speculated that monocyte PECAM-1-endothelial cell PECAM-1 homophilic interactions might contribute to endothelial cell survival. Further evidence that engagement of PECAM-1 can result in the transduction of a survival signal was provided by studies showing that the rate and extent of serum deprivation-induced apoptosis of endothelial cells is lessened if endothelial cells are first attached to immobilized PECAM-1/IgG 18 or treated with an anti-PECAM-1 monoclonal antibody. 19 While the latter investigation, like the study of Noble et al, found a correlation between PECAM-1-induced cell survival and increased transcript levels of the antiapoptotic gene, A1, the molecular mechanisms by which PECAM-1 might exert its cytoprotective effects have not to date been examined.Two major cell death pathways-termed the extrinsic and intrinsic pathways of apoptosis-exist in mammalian cells (reviewed by Hengartner 20 ). The extrinsic pathway is initiated by engagement and aggregation of tumor necrosis factor (TNF) family death receptors (such as The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. CD95/Fas) which, through a series of death domain-containing adaptor molecules, recruit and directly activate cytosolic caspase 8, which in turn converts procaspase 3 to caspase 3-the central executioner of the apoptotic process. Th...

Endothelial progenitor cells for cancer gene therapy

“…44-46 VE-cadherin 47 promotes EC survival, as does CD31 (platelet EC adhesion molecule (PECAM-1)). 48 aub3 triggers antiapoptotic nuclear factor-kB signaling after binding to ligands attached to the extracellular matrix. 49 However, the receptor switches to proapoptotic activity when triggered by ligands not anchored to the extracellular matrix.…”

Different susceptibilities of PECAM-deficient mouse strains to spontaneous idiopathic pneumonitis

“…On the other hand, the immune response must be terminated after the infection is cleared to prevent further tissue damage, and PECAM has also been shown to regulate programmed cell death (apoptosis) (Bird et al, 1999;Evans et al, 2001;Gao et al, 2003;Noble et al, 1999). PECAM has two cytoplasmic Immunoreceptor Tyrosine Inhibitory Motif (ITIM) domains for intracellular signaling (Newman et al, 2001;Newton-Nash and Newman, 1999).…”

“…When PECAM on live cells engages macrophage PECAM, phagocytosis is prevented. Signaling through the cytoplasmic tail and the ITIM domains is important for both preventing ingestion of live leukocytes and increasing resistance to apoptosis (Brown et al, 2002;Gao et al, 2003). Thus, PECAM function is important for both promoting and terminating inflammation.…”

Targeting PECAM-1 for anti-cancer therapy

“…7). The mechanisms of this protection against genotoxic agents appear to be distinct from the protection provided by PECAM-1 in response to other stimuli and in other cell types 20 and await further characterization.…”

“…[7][8][9] With respect to its potential activity in the pathogenesis of tumors, this cell adhesion and signaling molecule has been implicated in angiogenesis, 10-13 vascular permeability, 14 leukocyte (neutrophils and monocytes) recruitment out of the circulation [15][16][17] and endothelial resistance to endotoxic stress 18,19 and apoptotic insults. 20 Consequently, by inhibiting tumor neovascularization, altering vascular permeability, increasing endothelial susceptibility to apoptotic stress and limiting leukocyte infiltration within the tumor, antagonism of PECAM-1 could inhibit tumor growth independent of any direct effects on the tumor.…”