PECAM-1 Is a Modulator of STAT Family Member Phosphorylation and Localization: Lessons from a Transgenic Mouse

Abstract

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.

Enhanced Susceptibility to Endotoxic Shock and Impaired STAT3 Signaling in CD31-Deficient Mice

“…In STAT3-deficient hepatocytes, LPS does not induce a subset of IL-6-responsive, acute phase genes that may be important in recovery from endotoxic shock. 19 Our findings of dysregulated cytokine induction in PECAM-1-deficient mice following LPS challenge are consistent with the data presented in this report and our previous data, 8,24 suggesting that PECAM-1 serves as a scaffolding on which STAT isoforms are differentially phosphorylated, providing a regulatory mechanism of STAT signaling; and on which the phosphatase SHP-2, known to be involved in IL-6 signaling, can be sequestered, modulating its activity. Indeed, inhibition of phosphatase activity (by sodium orthovanadate) during IL-6 stimulation of lymphocytes elicits a blunting of the dephosphorylation of pYSTAT3 in CD31 KO splenocytes, resulting in pSTAT3 levels in the CD31 KO splenocytes that more closely approximate those of the WT splenocytes (% pSTAT3 relative to WT ϭ 14.3% Ϯ 5.56 without sodium orthovanadate versus 70.1% Ϯ 13 with the addition of sodium orthovanadate) (Figure 10).…”

“…6 -10 By serving a scaffolding function, it has been hypothesized that CD31 mediates tyrosine phosphorylation of two members of the STAT (signal transducers and activators of transcription) family, STAT3 and STAT5. 8 Based on its multiple roles in cell adhesion, leukocyte migration, and cell signaling, we reasoned that CD31 would also regulate the acute phase response (APR). Either infection or tissue injury can trigger the APR.…”

An Immunoreceptor Tyrosine Activation Motif in the Mouse Mammary Tumor Virus Envelope Protein Plays a Role in Virus-Induced Mammary Tumors

“…PECAM-1, the endothelial adhesion receptor, was also thought to contain an ITAM, although more recent data suggests that it functions as an immunoreceptor tyrosine inhibitory motif (23). Interestingly, mammary tissue expression of PECAM-1 in transgenic mice led to attenuated mammary gland development (22). Recent work has also shown that Syk, a downstream target of ITAM signaling, is expressed in normal human breast cells but not in invasive breast carcinoma and that it acts as a growth suppressor when introduced into the latter (6).…”

Role of CD31/Platelet Endothelial Cell Adhesion Molecule-1 Expression in in Vitro and in Vivo Growth and Differentiation of Human Breast Cancer Cells

“…39 Evidence supporting this hypothesis comes from the ectopic expression of CD31 in transgenic mice, which affects early events of mammary gland morphogenesis, suggesting that it may regulate the ductal branching at early stages of embryogenesis. 40 Evidence against this hypothesis comes from the lack of CD31 expression by nonneoplastic human breast tissue at different stages of development. 41,42 Thus, CD31 expression in breast cancer might be the result of gene amplification, as suggested by the observation that 17q23 (the region of the chromosome where CD31 gene is localized 43 ) is frequently amplified in breast carcinomas.…”