RhoGEFs as signaling platforms of chemotactic GPCRs
Cancer cells and stroma cells in tumors secrete chemotactic agonists that exacerbate invasive behavior, promote tumor-induced angiogenesis, and recruit protumoral bone marrow-derived cells. In response to shallow gradients of chemotactic stimuli recognized by G protein-coupled receptors (GPCRs), Gbg-dependent effectors such as Phosphoinositide-3-kinases and Rac guanine nucleotide exchange factors, such as P-Rex1, contribute to the activation of Rho GTPases and their cytoskeletal-remodeling effectors. P-Rex1, as many other Rho guanine nucleotide exchange factors coexpressed in protumoral cells, is a multidomain protein that interacts with multiple regulators and upstream signaling partners. The role of P-Rex1 as a signaling platform of chemotactic GPCRs will be discussed based on its interactions with GPCRs, Gbg and the serine/threonine kinases mTOR and PKA. Overall, the proven relevance of multiple chemokines in oncogenic settings has pointed to RhoGEFs as potential pharmacologic targets in cancer research.
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