title: 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.
authors.affiliation: College of Arts and Sciences, Marian University Indianapolis, Indianapolis, Indiana, United States of America.
authors.forename: Colleen L
authors.identifier: http://orcid.org/0000-0002-7689-6697
authors.initials: CL
authors.lastname: Doçi
authors.affiliation: Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America.
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Mikelis
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Callejas-Valera
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Karina K
authors.initials: KK
authors.lastname: Hansen
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.|PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Pharmacology, Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006706:Homeostasis; D015603:Keratinocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014945:Wound Healing
chemical_list: D043802:GTP-Binding Protein alpha Subunits, Gq-G11