TRIP6 Regulates p27KIP1 To Promote Tumorigenesis

TRIP6 is an adaptor protein that regulates cell motility and antiapoptotic signaling. Although it has been implicated in tumori-genesis, the underlying mechanism remains largely unknown. Here we provide evidence that TRIP6 promotes tumorigenesis by serving as a bridge to promote the recruitment of p27KIP1 to AKT in the cytosol. TRIP6 regulates the membrane translocation and activation of AKT and facilitates AKT-mediated recognition and phosphorylation of p27KIP1 specifically at T157, thereby promoting the cytosolic mislocalization of p27KIP1. This is required for p27KIP1 to enhance lysophosphatidic acid (LPA)-induced ovarian cancer cell migration. TRIP6 also promotes serum-induced reduction of nuclear p27KIP1 expression levels through Skp2-dependent and-independent mechanisms. Consequently, knockdown of TRIP6 in glioblastoma or ovarian cancer xenografts restores nuclear p27KIP1 expression and impairs tumor proliferation. As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas. Thyroid hormone receptor-interacting protein 6 (TRIP6) is azyxin-related adaptor protein and focal adhesion molecule (1). Through its three LIM domains, PDZ-binding motif, Crk SH2-binding motif, and several putative SH3-binding domains, TRIP6 associates with a variety of molecules from the cell surface to the nucleus to regulate actin reorganization, focal adhesio