Molecular Mechanism of KAI1/CD82-mediated Suppression

KAI1/CD82介导的抑制的分子机制

• 批准号: 7937533
• 负责人: XIN A ZHANG
• 金额: $ 4.64万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937533
• 关键词: Actins; Acylation; Adhesions; Affect; Binding; Binding Proteins; Biochemical; Biological Process; Cell physiology; Classification; Complex; Cytoplasmic Tail; Cytoskeleton; 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; therapeutic development; 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.

KAI 1/CD 82是四跨膜蛋白超家族的成员，并已被重新发现为癌症 转移抑制因子但KAI 1/CD 82介导的肿瘤转移抑制机制尚不清楚。与其他四跨膜蛋白类似，KAI 1/CD 82已被报道调节细胞迁移和癌细胞侵袭。我们的研究表明：1）前列腺癌细胞中KAI 1/CD 82表达的恢复抑制细胞运动性，2）FAK-p130 CAS/CrK-桩蛋白信号通路是KAI 1/CD 82介导的前列腺癌细胞运动性抑制所必需的，3）KAI 1/CD 82破坏运动性相关亚细胞结构如粘着斑和皮质肌动蛋白网络的形成，4）KASP（或EWI 2/PGRL）是一种新的IG超家族蛋白，被鉴定为KAI 1/CD 82结合蛋白;（5）KASP（或EWI 2/PGRL）在细胞迁移中与KAI 1/CD 82功能性协同。因此，我们假设KAI 1/CD 82介导的对癌症转移的抑制依赖于其通过1）调节控制细胞运动的细胞内信号传导途径和2）参与参与细胞运动的跨膜复合物来抑制细胞运动。因此，我们建议首先确定KAI 1/CD 82分子中负责抑制细胞运动性和侵袭性的结构和功能元件。具体地，将确定特定生物化学特征如酰化、内化和KASP（或EW 12/PGRL）关联在癌细胞运动性和侵袭性中的作用，以便最终将KAI 1/CD 82的特定生物化学特征与其对细胞运动性的抑制联系起来。第二，我们将评估 KASP（或EWI 2/PGRL）在KAI 1/CD 82介导的癌细胞运动性和侵袭性抑制中的作用。第三，我们将通过分析细胞运动相关的细胞功能，如粘附、铺展和囊泡运输以及细胞运动相关的分子信号传导，评估运动抑制所需的生化特征如何影响细胞运动。总之，这些研究将确定负责KAI 1/CD 82介导的癌症转移抑制的机制。了解KAI 1/CD 82在癌细胞运动中的机制作用将有望导致能够特异性抑制肿瘤细胞运动的治疗剂的开发。 癌症转移