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

血小板内皮细胞粘附分子-1（PECAM-1-CD 31）是Ig超家族的成员，其涉及多种生物学反应，例如白细胞迁移、血管生成、细胞信号传导、细胞粘附和迁移。该实验室最近的研究表明，PECAM-1含有胞质内免疫受体酪氨酸基序（ITIM），磷酸化后可通过募集和激活蛋白酪氨酸磷酸酶SHP-1和SHP-2介导抑制功能。因此，我们认为PECAM-1是一个新兴的Ig-ITIM超家族的新成员。Ig-ITIM基因家族的成员具有两种毒性-非抑制性受体，其在连接特异性受体后可在B细胞、T细胞、肥大细胞、内皮细胞或血小板的情况下全面刺激或抑制细胞活化。平衡细胞活化的阈值在对肿瘤、病原体或过敏原的免疫应答中是至关重要的，以阻止自身免疫性和传染性疾病，激发疫苗接种的免疫记忆，并抑制血小板活化的程度和持续时间。我们的研究集中在PECAM-1家族成员的分离和功能特性，以确定其在调节血管和造血细胞中的细胞信号通路中的作用。我们预测PECAM-1具有许多未定义的家族成员，其作为单独基因的产物作为多个同种型存在，离散外显子的选择性剪接和单点突变引起保守和非转换性氨基酸变化。这项研究的长期潜力是为理解PECAM-1亚型在健康和疾病中的生理细胞中的结构和功能作用提供知识。这些知识可以应用于自身免疫性疾病、体液和炎症反应的临床管理中，为新的治疗干预提供靶点。

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.