Structural and functional properties of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) Isoforms

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Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protein tyrosine phosphatases, SHP-1 and SHP-2. We would therefore consider PECAM-1 as a new member of an emerging Ig-ITIM superfamily. Members of the Ig-ITIM gene family have both inhibitory-non-inhibitory receptors which upon ligation of specific receptors can globally stimulate or inhibit cellular activation in the context of B cells, Tcells, mast cells , endothelial cells or platelets. Balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease, to provoke immunological memory from vaccination and to dampen the extent and duration of platelet activation. Our investigations are focussing on the isolation and functional characterisation of PECAM-1 family members to define their role in regulating cell signaling pathways in vascular and haematopoietic cells. We predict that PECAM-1 has numerous undefined family members that exist as multiple isoforms as a product of separate genes, alternative splicing of discrete exons and single point mutations giving rise to conservative and non-conversative amino acid changes. The longer term potential of this study is to provide knowledge for understanding the structural and functional roles of PECAM-1 isoforms in physiological cells in health and disease. This knowledge could then be applied to provide targets for novel therapeutic interventions in the clinical management of autoimmune disease, humoral and inflammatory responses.