TRE17 links actin remodeling & vesicle trafficking

TRE17 连接肌动蛋白重塑

• 批准号: 7027024
• 负责人: Margaret Mary Chou
• 金额: $ 31.59万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027024
• 关键词: actins; biological transport; calcium; cell migration; cell transformation; confocal scanning microscopy; guanine nucleotide exchange factors; guanosinetriphosphatases; neoplasm /cancer invasiveness; oncogenes; phenotype; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): Acquisition of a motile, invasive phenotype is a key step in malignant transformation. The Rho family GTPases Cdc42 and Rac1 play a central role in this process by regulating dynamic actin remodeling and vesicular trafficking, coordination of which is essential for cell movement and invasiveness. Cdc42 and Rac1 act by promoting formation of filopodia and lamellapodia, respectively, at the leading edge of a motile cell, and invadopodia at the ventral surface. My laboratory has identified a novel effector of Cdc42 and Rac1, the TRE17 oncogene (a.k.a. USP6), which we hypothesize coordinates actin remodeling and targeted vesicular trafficking. TRE17 has been implicated in tumorigenesis in both humans and mice, yet little is known of its molecular functions. We have identified two direct targets of TRE17, IQGAP1 and the Arf6 GTPase, both of which have previously been linked to motile and invasive behavior. Indeed, high IQGAP1 expression has been linked to invasiveness in carcinomas. IQGAP1 directly regulates actin remodeling, while Arf6 controls endocytosis and plasma membrane recycling. Our preliminary data further identifies calcium/calmodulin (Ca2+/CaM) as an allosteric regulator of TRE17. We hypothesize that TRE17 induces motile, invasive behavior through simultaneous regulation of actin remodeling through IQGAP1 and vesicular trafficking through Arf6, in a manner that is regulated by Ca2+. Through this work we hope to understand how these functions are coordinated during cell movement, and to elucidate the mechanism of TRE17 transformation.

描述（由申请人提供）：运动性、侵袭性表型的获得是恶性转化的关键步骤。 Rho 家族 GTPases Cdc42 和 Rac1 通过调节动态肌动蛋白重塑和囊泡运输在此过程中发挥核心作用，其中的协调对于细胞运动和侵袭至关重要。 Cdc42 和 Rac1 通过分别促进运动细胞前缘的丝状伪足和板状伪足以及腹侧表面的侵袭伪足的形成来发挥作用。我的实验室已经鉴定出 Cdc42 和 Rac1 的一种新型效应子，即 TRE17 癌基因（又名 USP6），我们假设它协调肌动蛋白重塑和靶向囊泡运输。 TRE17 与人类和小鼠的肿瘤发生有关，但对其分子功能知之甚少。我们已经确定了 TRE17 的两个直接靶点：IQGAP1 和 Arf6 GTPase，这两个靶点之前都与运动和侵入行为有关。事实上，IQGAP1 高表达与癌症的侵袭性有关。 IQGAP1 直接调节肌动蛋白重塑，而 Arf6 控制内吞作用和质膜回收。我们的初步数据进一步确定钙/钙调蛋白 (Ca2+/CaM) 是 TRE17 的变构调节剂。我们假设 TRE17 通过 IQGAP1 同时调节肌动蛋白重塑和通过 Arf6 调节囊泡运输，以一种受 Ca2+ 调节的方式诱导运动性、侵入性行为。通过这项工作，我们希望了解这些功能在细胞运动过程中是如何协调的，并阐明TRE17转化的机制。