title: Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector.
abstract: Heterotrimeric G proteins play an essential role in the initiation of G protein-coupled receptor (GPCR) signaling through specific interactions with a variety of cellular effectors. We have recently reported that GPCR activation promotes a direct interaction between Gαq and protein kinase C ζ (PKCζ), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLCβ. We report herein that the activation-dependent Gαq/PKCζ complex involves the basic PB1-type II domain of PKCζ and a novel interaction module in Gαq different from the classical effector-binding site. Point mutations in this Gαq region completely abrogate ERK5 phosphorylation, indicating that Gαq/PKCζ association is required for the activation of the pathway. Indeed, PKCζ was demonstrated to directly bind ERK5 thus acting as a scaffold between Gαq and ERK5 upon GPCR activation. The inhibition of these protein complexes by G protein-coupled receptor kinase 2, a known Gαq modulator, led to a complete abrogation of ERK5 stimulation. Finally, we reveal that Gαq/PKCζ complexes link Gαq to apoptotic cell death pathways. Our data suggest that the interaction between this novel region in Gαq and the effector PKCζ is a key event in Gαq signaling.
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain, Instituto de Investigación Sanitaria La Princesa, 29006-Madrid, Spain, Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Guzmán
authors.initials: G
authors.lastname: Sánchez-Fernández
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain, Instituto de Investigación Sanitaria La Princesa, 29006-Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Cabezudo
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain, Instituto de Investigación Sanitaria La Princesa, 29006-Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Caballero
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain, Instituto de Investigación Sanitaria La Princesa, 29006-Madrid, Spain.
authors.forename: Carlota
authors.initials: C
authors.lastname: García-Hoz
authors.affiliation: Departments of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, and.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Tall
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Klett
authors.affiliation: Département de Biochimie, Université de Montréal, C.P. 6128, Succursale centre-ville, Montréal, Québec, H3C 3J7 Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Michnick
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain, Instituto de Investigación Sanitaria La Princesa, 29006-Madrid, Spain, fmayor@cbm.csic.es.
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.affiliation: From the Departamento de Biología Molecular and Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Universidad Autónoma de Madrid, 28049-Madrid, Spain, Instituto de Investigación Sanitaria La Princesa, 29006-Madrid, Spain, cribas@cbm.csic.es.
authors.forename: Catalina
authors.initials: C
authors.lastname: Ribas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D054768:G-Protein-Coupled Receptor Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D048054:Mitogen-Activated Protein Kinase 7; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta
keywords: ERK5; G protein; G protein-coupled receptor (GPCR); G protein-coupled receptor kinases; Gαq; PB1 domain; PKCζ; mitogen-activated protein kinase (MAPK); regulator of G protein signaling (RGS); signal transduction