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

Abstract

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, Gαq and Gα11, 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 Gα11 and Gαq from endothelial cells impairs the Rho-mediated formation of focal adherens junctions, suggesting that Gα11/q signaling may also play a significant role in cytoskeletal-mediated cellular responses in epithelial cells. Indeed, combined deletion of Gα11 and Gαq 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 Gαq-null keratinocytes under combined Gα11 deficiency. In fact, cells lacking Gα11/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 Gα11/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 Gα11/q signaling, implicating its upstream regulation as a potential therapeutic target in a host of pathologic conditions.

Cell‐permeable high‐affinity tracers for Gq proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors

“…Tumours with high G q levels may profit from treatment with G q protein-inhibiting drugs. Gα q expression levels may also be altered in autoimmune diseases, such as rheumatoid arthritis (Zhang & Shi, 2016), and the expression level of Gα q proteins appears to be related to inflammatory diseases, for example in the lung (John et al, 2016), to pathological conditions of the skin (Doçi et al, 2017) and even to heart diseases (Frey et al, 2017).…”

Genome Editing Provides New Insights into Receptor-Controlled Signalling Pathways

“…Interestingly, lack of expression of Gq and G11 did not affect cell viability or proliferation [18]. However, compared to parental HEK293 cells migration towards foetal bovine serum of the cells lacking both Gq and G11 is markedly impaired [19]. Re-introduction of Gq into the Gq/G11-knock out cells enhanced the migration response to transforming growth factor- (TGF-), while both cell lines showed a similar signalling response (SMAD phosphorylation)…”

Progesterone receptors in normal breast development and breast cancer

“…These results support the concept that PRA-H tumors respond to endocrine treatments. CK5 and Ki-67 expression were evaluated using immunohistochemical techniques using a double staining protocol in a tissue microarray as described [192]. A CK5+ PR negative tumor sample is shown as CK5+ control (upper panel).…”

“…Figure 3. CK5 and Ki-67 expression in breast cancer xenografts of cells expressing only PRA (T47D-YA) or PRB (T47D-YB)CK5 and Ki-67 expression were evaluated using immunohistochemical techniques using a double staining protocol in a tissue microarray as described[192]. A CK5+ PR negative tumor sample is shown as CK5+ control (upper panel).…”