Figure 1
The many facets of PECAM-1 signaling: a schematic representation of PECAM-1’s roles as a dynamic modulator of endothelial, hematopoietic precursor cell and immune cell junctional, cytoskeletal, adhesive, and signaling pathways based on data accrued in the laboratory (1) illustrates the binding of SHP-1 & -2 to differentially phosphorylated/alternatively spliced PECAM-1, resulting in distinct binding to PECAM-1 and substrate specificities. PECAM-1/SHP-1 & 2 interactions have been shown to modulate moesin phosphorylation, affecting directed migration of neutrophils and megakaryocytes; the tyrosine phosphorylation state of beta catenin and FAK (not shown), affecting vascular permeability, proliferation, apoptosis, gene expression and migration; activation state of ERK1/2, affecting STAT phosphorylation and cytokine responsiveness, in turn affecting vascular permeability, proliferation, apoptosis, gene expression and migration; tyrosine phosphorylation state of STAT3, affecting cytokine induction. (2) illustrates the interaction of PECAM-1 with Gai2, affecting Rho activation and cell motility and migration; (3) illustrates the modulation of MMP-2 & -9 expression by the presence of PECAM-1 on the surface of endothelial cells via induction and nuclear targeting of GATA2 and p53 transcription factors; (4) illustrates PECAM-1's interactions with PI3K that modulates Akt activity, which in turn regulates Egr-1 expression via p38 activation, leading to blunting of tissue factor induction, reducing thrombosis, permeability and apoptosis in endothelial cells; illustrates PECAM-1/PI3K interactions that also regulate GSK-3beta activity via Akt phosphorylation, resulting in blunting of beta catenin serine phsophorylation, reducing its proteosomal degradation; (5) illustrates tyrosine phosphorylated beta catenin binding to PECAM-1, resulting in sequestration of beta catenin, rendering it incapable of binding to VE-cahderin, affecting junction formation; (6) illustrates the binding of gamma catenin to exon 13 of PECAM-1, dependent upon the phosphorylation state of PECAM-1 residue S674.