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）：获取运动，侵入性表型是恶性转化的关键步骤。 Rho家族GTPASE CDC42和RAC1通过调节动态肌动蛋白的重塑和囊泡运输，在此过程中起着核心作用，其协调对于细胞运动和侵入性至关重要。 Cdc42和Rac1通过促进丝状细胞的前缘和腹侧表面的Invadopodia的形成分别促进了丝状和薄片的形成。我的实验室已经确定了CDC42和RAC1的新型效应子，Tre17癌基因（又称USP6），我们假设坐标是肌动蛋白重塑并靶向囊泡运输。 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，IQGAP1和ARF6 GTPase的两个直接靶标，它们以前都与运动和入侵行为链接。实际上，高IQGAP1表达与癌中的侵袭性有关。 IQGAP1直接调节肌动蛋白的重塑，而ARF6控制内吞作用和质膜回收。我们的初步数据进一步将钙/钙调蛋白（CA2+/CAM）确定为TRE17的变构调节剂。我们假设TRE17通过通过Ca2+调节的方式通过IQGAP1和囊泡运输通过同时调节肌动蛋白通过IQGAP1和囊泡运输来诱导运动，侵入性行为。通过这项工作，我们希望了解在细胞运动过程中如何协调这些功能，并阐明TRE17转化的机制。