Epidermal loss of Galphaq confers a migratory and differentiation defect in keratinocytes

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, Galphaq and Galpha11, 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 Galpha11 and Galphaq from endothelial cells impairs the Rho-mediated formation of focal adherens junctions, suggesting that Galpha11/q signaling may also play a significant role in cytoskeletal-mediated cellular responses in epithelial cells. Indeed, combined deletion of Galpha11 and Galphaq 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 Galphaq-null keratinocytes under combined Galpha11 deficiency. In fact, cells lacking Galpha11/q 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 Galpha11/q 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 Galpha11/q signaling, implicating its upstream regulation as a potential therapeutic target in a host of pathologic conditions.

• Doci, C. L.
• Mikelis, C. M.
• Callejas-Valera, J. L.
• Hansen, K. K.
• Molinolo, A. A.
• Inoue, A.
• Offermanns, S.
• Gutkind, J. S.