CEACAM1 (CD66a) Promotes Human Monocyte Survival via a Phosphatidylinositol 3-Kinase- and AKT-dependent Pathway

Qigui Yu, Edith M. C. Chow, Henry Wong, Jenny Gu, Ofer Mandelboim, Scott D. Gray-Owen, Mario A. Ostrowski
2006 Journal of Biological Chemistry  
CEACAM1 (also known as CD66a) is a transmembrane glycoprotein that mediates homophilic intercellular interactions that influence cellular growth, immune cell activation, and tissue morphogenesis. Various studies have suggested a link between CEACAM1 and cellular apoptosis, including a recent demonstration that ERK1/2 signaling is triggered downstream of CEACAM1. In this study, we reveal that CEACAM1-long binding confers survival signals to human peripheral blood mononuclear cells.
more » ... ells. CEACAM-specific antibodies effectively protected peripheral blood mononuclear cells from apoptosis, with this effect being particularly dramatic for primary monocytes that undergo spontaneous apoptosis during in vitro culture. This protective effect was reiterated when using soluble CEACAM1, which binds to cell-surface CEACAM1 via homophilic interactions. Monocyte survival correlated with a CEACAM1-dependent up-regulation of the cellular inhibitor of apoptosis Bcl-2 and the abrogation of caspase-3 activation. CEACAM1 binding triggered a phosphatidylinositol 3-kinase-dependent activation of the protein kinase Akt without influencing the activity of extracellular signal-related kinase ERK, whereas the phosphatidylinositol 3-kinase-specific inhibitor LY294002 effectively blocked the protective effect of CEACAM1. Together, this work indicates that CEACAM1 confers a phosphatidylinositol 3-kinase-and Akt-dependent survival signal that inhibits mitochondrion-dependent apoptosis of monocytes. By controlling both ERK/MEK and PI3K/Akt pathways, CEACAM1 functions as a key regulator of contact-dependent control of cell survival, differentiation, and growth. Recent evidence suggests that the effect of CEACAM1 on immune cell function depends upon the isoform expressed. Differential splicing of CEACAM1 transcript generates either a long (73 amino acids) cytoplasmic domain-containing CEACAM1-L, which contains two immunoreceptor tyrosinebased inhibitory motifs (ITIMs) 3 that inhibit cellular growth
doi:10.1074/jbc.m608864200 pmid:17071610 fatcat:gkveld4aszcptkoyq6yffhh7yy