Platelet-endothelial cell adhesion molecule (PE-CAM)-1 is a 130-kDa glycoprotein commonly used as an endothelium-specific marker. Evidence to date suggests that PECAM-1 is more than just an endothelial cell marker but is intimately involved in signal transduction pathways. This is mediated in part by phosphorylation of specific tyrosine residues within the ITAM domain of PECAM-1 and by recruitment of adapter and signaling molecules. Recently we demonstrated that PECAM-1/␤-catenin association functions to regulate ␤-catenin localization and, moreover, to modulate ␤-catenin tyrosine phosphorylation levels. Here we show that: 1) not only ␤-catenin, but also ␥-catenin is associated with PE-CAM-1 in vitro and in vivo; 2) PKC enzyme directly phosphorylates purified PECAM-1; 3) PKC-derived PECAM-1 serine/threonine phosphorylation inversely correlates with ␥-catenin association; 4) PECAM-1 recruits ␥-catenin to cell-cell junctions in transfected SW480 cells; and 5) ␥-catenin may recruit PECAM-1 into an insoluble cytoskeletal fraction. These data further support the concept that PECAM-1 functions as a binder and modulator of catenins and provides a molecular mechanism for previously reported PECAM-1/cytoskeleton interactions.Platelet-endothelial cell adhesion molecule (PECAM-1, CD31) 1 is a 130-kDa glycoprotein belonging to the Ig superfamily of cell adhesion molecules. PECAM-1 expression is restricted to cells of the vascular system platelets, monocytes, neutrophils, selected T cells, and endothelial cells (1). In the latter, PECAM-1 is localized to cell-cell borders of confluent monolayers and, in addition, to lumen-facing areas of blood vessels or tube-like endothelial structures formed in vitro (2). PECAM-1 becomes diffusely distributed on the cell surface of sparse cell cultures or at the leading fronts of migrating cells (3). PECAM-1 has been shown to be a key player in the adhesion cascade leading to extravasation of leukocytes during inflammation. Pretreatment of monocytes or neutrophils, as well as endothelial cells, with anti-PECAM-1 antibodies effectively inhibited transmigration in vitro (4) and in vivo (5), indicating that PECAM-1 molecules on both the endothelial cells and the leukocytes contribute to the transmigration process. This was further supported by a genetic approach in PECAM-1 knockout mice, in which leukocytes are transiently arrested between the vascular endothelium and the basement membrane of inflammatory sites (6). In addition, PECAM-1 knockout mice have been noted to suffer from prolonged bleeding times, which is at least in part due to disrupted endothelial-platelet interactions (53), supporting the role of PECAM-1 as mediator of cell adhesion/activation. PECAM-1 has been shown to be more than just a passive player in adhesive interactions and indeed is actively involved in signal transduction pathways. PECAM-1 was demonstrated to undergo phosphorylation on tyrosine residues following mechanical (7) or biochemical (8 -10) stimulation. Specifically, an immunoreceptor tyrosine-based activati...

PECAM-1 (CD31) is a member of the immunoglobin (Ig) superfamily of cell adhesion molecules whose expression is restricted to hematopoietic and vascular cells. PECAM-1 can recruit adapter and signaling molecules via its immunoreceptor tyrosine activation motif (ITAM), suggesting that PECAM-1 plays a role in signal transduction pathways. To study the involvement of PECAM-1 in signaling cascades in vivo, we used the major histocompatibility (MHC) I gene promoter to target ectopic PECAM-1 expression in transgenic mice. We noted an attenuation of mammary gland development at early stages of virgin ductal branching morphogenesis. STAT5a, a modulator of milk protein gene expression during lactation, was localized to the nuclei of ductal epithelial cells of 6-week-old virgin PECAM-1 transgenics, but not in control mice. This correlated with decreases in ductal epithelial cell proliferation and induction of p21, an inhibitor of cell cycle progression. Using in vitro model systems we demonstrated PECAM-1/STAT5a association and found that residue Y701 in PECAM-1's cytoplasmic tail is important for PECAM-1/STAT5 association and that PECAM-1 modulates increases in STAT5a tyrosine phosphorylation levels. We suggest that by serving as a scaffolding, PECAM-1 can bring substrates (STAT5a) and enzymes (a kinase) into close proximity, thereby modulating phosphorylation levels of selected proteins, as previously noted for beta-catenin.