TRE17 links actin remodeling & vesicle trafficking

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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.