TRE17 links actin remodeling & vesicle trafficking

描述（由申请人提供）：获得可移动的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重塑和囊泡运输在这一过程中发挥核心作用，其协调对细胞运动和侵袭性至关重要。Cdc42和Rac1分别在运动细胞的前缘促进丝状足和板足的形成，在腹面促进侵入足的形成。我的实验室已经确定了Cdc42和Rac1的一种新的效应物，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袭行为有关。事实上，高IQGAP1表达与癌症的侵袭性有关。IQGAP1直接调控肌动蛋白重塑，而Arf6控制胞吞作用和质膜再循环。我们的初步数据进一步确定钙/钙调素（Ca2+/CaM）是TRE17的变构调节因子。我们假设TRE17通过同时通过IQGAP1调节肌动蛋白重塑和通过Arf6调节囊泡运输，以Ca2+调节的方式诱导运动性、侵袭性行为。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。

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.