Molecular mechanisms of immune cell motility and chemotaxis

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In previous work, we have investigated the roles the Rho subfamily of Rho GTPases (RhoA, RhoB and RhoC) in the cell shape, motility and chemotaxis of mouse macrophages and human monocytes. In addition, we have generated myeloid-restricted Cdc42 knockout mice and investigated the roles of Cdc42 in macrophage cell shape and chemotaxis. More recently, in preliminary work, we have shown that Gαi2 (encoded by Gnai2) is essential for complement C5a-mediated chemokinesis and chemotaxis, but not complement C5a-induced Ca2+ signaling and cell spreading. In the current extension, we plan to identify the Gβ subunits and Gβgamma-activated RhoGEFs (Rho guanine nucleotide exchange factors) linking complement C5a receptors, G protein-coupled receptors (GPCRs), to Rho GTPases, the effectors of cytoskeletal rearrangements and motility/chemotaxis. Following completion of expression analysis, including next generation RNA sequence and Western blot analyses, we plan to investigate the roles of specific Gβ subunits and RhoGEFs using knockout mouse models which are currently available, pending lethality screening or in production. We speculate that the three-step signaling cascade Gβgamma-RhoGEF-Rho GTPase, which takes place on the plasma membrane, is the core of chemotactic signaling. Furthermore, we anticipate that our work will help to elucidate the minimal critical signal wiring of a single, albeit important, chemoattractant (complement C5a).