Epidermal loss of Gαq confers a migratory and differentiation defect in keratinocytes.
Colleen L DoçiConstantinos M MikelisJuan Luis Callejas-ValeraKarina K HansenAlfredo A MolinoloAsuka InoueStefan OffermannsJ Silvio GutkindPublished in: PloS one (2017)
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.
Keyphrases
- wound healing
- endothelial cells
- stem cells
- signaling pathway
- neoadjuvant chemotherapy
- squamous cell carcinoma
- cell proliferation
- radiation therapy
- pi k akt
- cancer therapy
- cell cycle arrest
- single molecule
- protein kinase
- cell death
- transcription factor
- epithelial mesenchymal transition
- locally advanced
- oxidative stress
- inflammatory response
- toll like receptor
- high glucose
- lymph node