Published In / Presented At
PLOS ONE (Vol.12, No.3)
Biochemistry, Biophysics, and Structural Biology | Molecular Biology | Structural Biology
G-protein coupled receptors (GPCRs), which activate heterotrimeric G proteins, are an essential class of transmembrane receptors that are responsible for a myriad of signaling events in normal and pathologic conditions. Two members of the G protein family, Gaq and Ga-11, activate one of the main GPCR pathways and function as oncogenes by integrating mitogen-stimulated signaling cascades that are active under malignant conditions. Recently, it has been shown that targeted deletion of Ga-11 and Gaq from endothelial cells impairs the Rho -mediated formation of focal adherens junctions, suggesting that Gai vg signaling may also play a significant role in cytoskeletal-mediated cellular responses in epithelial cells. Indeed, combined deletion of Ga-11 and Gaq confers a significant migratory defect in keratinocytes that delays cutaneous wound healing in an in vivo setting. This delay can be attributed to a defect during the reepithelialization phase due to significantly attenuated migratory capacity of Gaq-null keratinocytes under combined Ga-11 deficiency. In fact, cells lacking Gaivg demonstrate a severely reduced ability to respond to mitogenic and migratory signals in the microenvironment, leading to inappropriate and premature terminal differentiation. These results suggest that Gaivg signaling pathways may be critical for integrating mitogenic signals and cytoskeletal function to achieve normal physiological responses. Emergence of a malignant phenotype may therefore arise from both under- and overexpression of Gai vg signaling, implicating its upstream regulation as a potential therapeutic target in a host of pathologic conditions.
Copyright all authors
Doci, Colleen L.; Mikelis, Constantinos M; Callejas-Valera, Juan Luis; Hansen, Karina K.; Molinolo, Alfredo A.; Inoue, Asuka; Offermanns, Stefan; and Gutkind, J. Slivio, "Epidermal Loss of Gag Confers a Migratory and Differentiation Defect in Keratinocytes" (2017). Department of Biology. 1.