Molecular Mechanism of KAI1/CD82-mediated Suppression

KAI1/CD82介导的抑制的分子机制

• 批准号: 7178435
• 负责人: XIN A ZHANG
• 金额: $ 21.8万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7178435
• 关键词: Actins; Acylation; Adhesions; Affect; Binding; Binding Proteins; Biochemical; Biological Process; Cell physiology; Classification; Complex; Cytoplasmic Tail; Cytoskeleton; Depth; Development; Diagnostic; Extracellular Domain; Focal Adhesions; Indium; Integral Membrane Protein; KAI1 gene; Lead; Link; Lysosomes; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metastasis Suppression; Metastatic Prostate Cancer; Molecular; Mutation; Neoplasm Metastasis; Palmitic Acylation Site; Proteins; Reporting; Role; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Subcellular structure; Therapeutic; Vesicle; cancer cell; cancer invasiveness; cell motility; human BCAR1 protein; human PHEMX protein; member; novel; palmitoylation; paxillin; restoration; trafficking; tumor progression

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.

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仍不清楚。与其他Tetraspanins类似，KAI1/CD82已被报道调节细胞迁移和癌细胞侵袭。我们的研究表明：1)KAI1/CD82表达的恢复抑制了细胞的运动，2)FAK-p130Cas/Crk-paxlin信号通路是KAI1/CD82介导的抑制前列腺癌细胞运动所必需的信号通路，3)KAI1/CD82破坏了与运动相关的亚细胞结构的形成，如局灶性黏附和皮质肌动蛋白网络，4)KASP(或EWI2/PGRL)，一个新的Ig超家族蛋白，被鉴定为KAI1/CD82结合蛋白，5)KASP(或EWI2/PGRL)在功能上与KAI/CD82在细胞迁移中协调。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和2)参与参与细胞运动的跨膜复合体而抑制细胞运动。因此，我们建议首先定义KAI1/CD82分子中负责抑制细胞运动和侵袭性的结构和功能元件。特别是，将确定特定的生化特征，如酰化、内化和KASP(或EWl2/PGRL)结合在癌细胞运动和侵袭力中的作用，以便最终将KAI1/CD82的特定生化特征与其抑制细胞运动联系起来。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，我们将通过分析细胞运动相关的功能，如黏附、铺展和囊泡运输以及细胞运动相关的分子信号，来评估运动抑制所需的生化特征(S)如何影响细胞运动。总之，这些研究将确定KAI1/CD82介导的抑制肿瘤转移的机制。了解KAI1/CD82在癌细胞运动中的机制作用将有助于开发能够特别抑制肿瘤细胞运动的治疗药物 癌症转移。