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

血小板内皮细胞黏附分子-1(PECAM-1-CD31)是免疫球蛋白超家族成员之一，参与多种生物学反应，如白细胞迁移、血管生成、细胞信号转导、细胞黏附和迁移等。本实验室最近的研究表明，PECAM-1含有胞浆内免疫受体酪氨酸抑制基序(ITIM)，在磷酸化后，可以通过募集和激活蛋白酪氨酸磷酸酶SHP-1和SHP-2来介导抑制功能。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基因家族的成员既有抑制性受体，也有非抑制性受体，当特定受体连接后，可以在B细胞、T细胞、肥大细胞、内皮细胞或血小板的背景下全面刺激或抑制细胞的激活。平衡细胞激活的阈值在对肿瘤、病原体或过敏原的免疫反应、阻止自身免疫和传染病、激发接种疫苗的免疫记忆以及抑制血小板激活的程度和持续时间方面至关重要。我们的研究集中在PECAM-1家族成员的分离和功能鉴定上，以确定它们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有许多未定义的家族成员，它们作为独立基因、离散外显子的选择性剪接和导致保守和非对话性氨基酸变化的单点突变的产物以多种异构体存在。这项研究的长期潜力是为理解PECAM-1亚型在健康和疾病中生理细胞中的结构和功能作用提供知识。这一知识随后可用于为自身免疫性疾病、体液反应和炎症反应的临床管理提供新的治疗干预措施的靶点。

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.