Molecular Mmechanism of KAI1/CD82-mediated Suppression

KAI1/CD82是Tetraspanin超家族的成员，已被重新发现为癌症 转移抑制因子。但KAI1/CD82介导的抑制肿瘤转移的机制 目前仍不清楚。与其他Tetraspanins类似，KAI1/CD82已被报道调节细胞迁移 以及癌细胞的侵袭性。我们的研究表明：1)KAI1/CD82的表达恢复 前列腺癌细胞抑制细胞运动，2)FAK-p130Cas/Crk-paxlin信号通路在前列腺癌中起重要作用 KAI1/CD82介导的前列腺癌细胞运动抑制，3)KAI1/CD82干扰前列腺癌的形成 与运动相关的亚细胞结构，如局灶性黏附和皮质肌动蛋白网络，4)KASP(或 EWI2/PGRL)是一个新的Ig超家族蛋白，被鉴定为KAI1/CD82结合蛋白，以及5)KASP (或EWI2/PGRL)在功能上与KAI-1/CD82协同作用于细胞迁移。因此，我们假设 KAI1/CD82介导的肿瘤转移抑制依赖于其通过 1)调节控制细胞运动的细胞内信号通路；2)参与 参与细胞运动的跨膜复合体。因此，我们建议首先定义结构和 KAI1/CD82分子中的功能元件负责抑制细胞的运动和侵袭。在……里面 特别是特定生化特征的作用，如酰化、内化和KASP(或 EWl2/PGRL)在癌细胞运动和侵袭力中的关联将被确定，以便最终确定 将KAI1/CD82的特定生化特征与其对细胞运动的抑制联系起来。第二，我们将评估 KASP(或EWI2/PGRL)在KAI1/CD82介导的抑制癌细胞运动和侵袭力中的作用 第三，我们将评估运动抑制所需的生化特征(S)如何通过以下方式影响细胞运动 分析与细胞运动相关的细胞功能，如黏附、扩散、囊泡运输和细胞 运动性相关的分子信号。总而言之，这些研究将确定导致 KAI1/CD82介导的肿瘤转移抑制作用理解KAI1/CD82的机制作用 癌细胞的运动将有望导致能够特别抑制的治疗方法的发展 癌症转移。

KAI1/CD82 is a member of the tetraspanin superfamily and has been re-discovered as a cancer metastasis suppressor. But the mechanism of the KAI1/CD82-mediated suppression of cancer metastasis still remains unclear. Similar to other tetraspanins, KAI1/CD82 has been reported to regulate cell migration and cancer cell invasiveness. Our studies indicate that: 1) restoration of the KAI1/CD82 expression in prostate cancer cells inhibits cell motility, 2) the FAK-p130CAS/CrK-paxillin signaling pathway is required for KAI1/CD82-mediated suppression of prostate cancer cell motility, 3) KAI1/CD82 disrupts the formation of motility-related subcellular structures such as focal adhesion and cortical actin network, 4) KASP (or EWI2/PGRL), a novel Ig superfamily protein, was identified as a KAI1/CD82-binding protein, and 5) KASP (or EWI2/PGRL) functionally coordinates with KAI 1/CD82 in cell migration. Therefore, we hypothesize that the KAI1/CD82-mediated suppression of cancer metastasis depends on its inhibition of cell motility through 1) regulating the intracellular signaling pathways that control cell movement, and 2) participating the transmembrane complex that is involved in cell movement. So, we propose to first define the structural and functional elements in KAI1/CD82 molecule responsible for the inhibition of cell motility and invasiveness. In particular, the roles of specific biochemical features such as acylation, internalization, and KASP (or EWl2/PGRL) association in cancer cell motility and invasiveness will be determined, in order to conclusively link a specific biochemical feature of KAI1/CD82 to its inhibition of cell motility. Second, we will assess the role of KASP (or EWI2/PGRL) in KAI1/CD82-mediated suppression of cancer cell motility and invasiveness. Third, we will assess how the biochemical feature(s) required for the motility-inhibition affects cell motility by analyzing cell motility-related cellular functions such as adhesion, spreading, and vesicle trafficking and cell motility-related molecular signaling. Together, these studies will identify the mechanism responsible for the KAI1/CD82-mediated suppression of cancer metastasis. Understanding the mechanistic roles of KAI1/CD82 in cancer cell motility will promises to lead to the development of therapeutics capable of specially inhibiting cancer metastasis.