Strength and duration of GIPC-dependent signaling networks as determinants in cancer

GIPC is a PDZ-domain containing adaptor protein that regulates the cell surface expression and endocytic trafficking of numerous transmembrane receptors and signaling complexes. Interactions with over 50 proteins have been reported to date including VEGFR, insulin-like growth factor-1 receptor (IGF-1R), GPCRs, and APPL, many of which have essential roles in neuronal and cardiovascular development. In cancer, a major subset of GIPC-binding receptors and cytoplasmic effectors have been shown to promote tumorigenesis or metastatic progression, while other subsets have demonstrated strong tumor-suppressive effects. Given that these diverse pathways are widespread in normal tissues and human malignancies, precisely how these opposing signals are integrated and regulated within the same tumor setting likely depend on the strength and duration of their interactions with GIPC. This review highlights the major pathways and divergent mechanisms of GIPC signaling in various cancers and provide a rationale for emerging GIPC-targeted cancer therapies.