PECAM-1 is a modulator of STAT family member phosphorylation and localization: Lessons from a transgenic mouse

PECAM-1 (CD31) is a member of the immunoglobin jig) superfamily of cell adh esion molecules whose expression is restricted to hematopoietic and vascula r cells. PECAM-1 can recruit adapter and signaling molecules via its immuno receptor tyrosine activation motif (ITAM), suggesting that PECAM-1 plays a role in signal transduction pathways. To study the involvement of PECAM-1 i n signaling cascades in vivo, we used the major histocompatibility (MHC) I gene promoter to target ectopic PECAM-1 expression in transgenic mice. We n oted an attenuation of mammary gland development at early stages of virgin ductal branching morphogenesis. STAT5a, a modulator of milk protein gene ex pression during lactation, was localized to the nuclei of ductal epithelial cells of 6-week-old virgin PECAM-1 transgenics, but not in control mice. T his correlated with decreases in ductal epithelial cell proliferation and i nduction of p21, an inhibitor of cell cycle progression. Using in vitro mod el systems we demonstrated PECAM-1/STAT5a association and found that residu e Y701 in PECAM-1's cytoplasmic tail is important for PECAM-1/STAT5 associa tion and that PECAM-1 modulates increases in STAT5a tyrosine phosphorylatio n levels. We suggest that by serving as a scaffolding, PECAM-1 can bring su bstrates (STAT5a) and enzymes (a kinase) into close proximity, thereby modu lating phosphorylation levels of selected proteins, as previously noted for beta -catenin. (C) 2001 Academic Press.