Functions and regulatory mechanisms of signaling pathways through G-proteins: a new interactome
Our laboratory is investigating key nodes in signalling networks involved in physiology and disease and the molecular mechanisms involved. G protein-coupled receptors (GPCR) are a family of hundreds of membrane proteins of key physiological and pharmacological importance. In particular, Gq-protein coupled receptors (Gq-GPCR) are increasingly being implicated in pathologies such as cardiovascular/metabolic diseases and cancer. In the last few years the interactome of Gαq (and the homologous Gα11 isoform) has expanded considerably with the description of novel effectors, contributing to improve our understanding of the cellular and physiological events controlled by this Gα subunit. Recently, our group has described a new adaptor role for Gq, important for the activations of ERK5 MAPK by Gq-coupled receptors as a novel PLCβ-independent signalling axis that relies upon the interaction between this G protein and two novel effectors (PKCζ and MEK5) through a novel acidic region in Gαq, different from the classical effector-binding region, and the PB1 domain of PKCζ. Moreover, Gαq is known to interact with several components of the cytoskeleton as well as with important organizers of membrane microdomains, which suggests that efficient signalling complexes might be confined to specific subcellular environments. The complex interaction network of Gαq underlies an ever-expanding functional diversity that puts forward this G alpha subunit as a major player in the control of physiological functions and in the development of different pathological situations.
The main focus of our research will be to understand how changes in Gq-GPCR signaling (involving different cell types and tissues) integrate at the cellular and organism level, and how they can foster disease progression, by using cellular and animal models with altered expression/activity of this protein, as well as samples from patients or animal models of disease. We will particularly focus on the functional impact of the novel interactions of Gαq with PB1-domain containing proteins, and its modulation by accesory proteins (as GRKs, AGS, RGS, EBP50, Ric8) in cell death, integration of nutrient sensing/autophagy signals and oxidative stress processes in the development of cardiovascular/metabolic diseases and cancer.
Fig 1. Gαq-signaling networks
|Last name||Name||Laboratory||Ext.*||Professional category|
|Navarro Lérida||Inmaculada||304||4728||Profesor Ayudante Doctor Universidad|
|Ribas Núñez||Catalina||304||4728||cribas(at)cbm.csic.es||Profesor Titular Universidad, GA|
|Sanz Flores||María||304||4652||maria.sanz(at)cbm.csic.es||Titulado Superior Grado de Doctor|
- Gαq activation modulates autophagy by promoting mTORC1 signaling. Cabezudo S, Sanz-Flores M, Caballero A, Tasset I, Rebollo E, Diaz A, Aragay AM, Cuervo AM, Mayor F Jr, Ribas C. Nature Comm. 2021 Jul 27;12(1):4540. doi: 10.1038/s41467-021-24811-4.
- G-protein-coupled receptor kinase 2 safeguards epithelial phenotype in head and neck squamous cell carcinomas. Palacios-García J, Sanz-Flores M, Asensio A, Alvarado R, Rojo-Berciano S, Stamatakis K, Paramio JM, Cano A, Nieto MÁ, García-Escudero R, Mayor F Jr, Ribas C. Int J Cancer. 2019 Dec 18. doi: 10.1002/ijc.32838.
- G protein-coupled receptor kinase 2 (GRK2) as a multifunctional signaling hub. Penela P, Ribas C, Sánchez-Madrid F, Mayor F Jr. Cell Mol Life Sci. 2019 Nov;76(22):4423-4446. doi: 10.1007/s00018-019-03274-3.
- Gαq signalling: the new and the old. Sánchez-Fernández G, Cabezudo S, García-Hoz C, Benincá C, Aragay AM, Mayor F Jr, Ribas C. Cell Signal. 2014 May;26(5):833-48. doi: 10.1016/j.cellsig.2014.01.010.
- G protein-coupled receptor kinases (GRKs) in tumorigenesis and cancer progression: GPCR regulators and signaling hubs. Nogués L, Palacios-García J, Reglero C, Rivas V, Neves M, Ribas C, Penela P, Mayor F Jr. Semin Cancer Biol. 2018 Feb;48:78-90. doi: 10.1016/j.semcancer.2017.04.013.
Protein Kinase C ζ Interacts with a Novel Binding Region of Gαq to Act as a Functional Effector. Sánchez-Fernández G, Cabezudo S, Caballero Á, García-Hoz C, Tall GG, Klett J, Michnick SW, Mayor F Jr, Ribas C. J Biol Chem. 2016 Apr 29;291(18):9513-25. doi: 10.1074/jbc.M115.684308.
- ERK5 activation by Gq-coupled muscarinic receptors is independent of receptor internalization and β-arrestin recruitment. Sánchez-Fernández G, Cabezudo S, García-Hoz C, Tobin AB, Mayor F Jr, Ribas C. PLoS One. 2013 Dec 17;8(12):e84174. doi: 10.1371/journal.pone.0084174.
- Protein kinase C (PKC)ζ-mediated Gαq stimulation of ERK5 protein pathway in cardiomyocytes and cardiac fibroblasts. García-Hoz C, Sánchez-Fernández G, García-Escudero R, Fernández-Velasco M, Palacios-García J, Ruiz-Meana M, Díaz-Meco MT, Leitges M, Moscat J, García-Dorado D, Boscá L, Mayor F Jr, Ribas C. J Biol Chem. 2012 Mar 2;287(10):7792-802. doi: 10.1074/jbc.M111.282210.
- G alpha(q) acts as an adaptor protein in protein kinase C zeta (PKCzeta)-mediated ERK5 activation by G protein-coupled receptors (GPCR). García-Hoz C, Sánchez-Fernández G, Díaz-Meco MT, Moscat J, Mayor F, Ribas C. J Biol Chem. 2010 Apr 30;285(18):13480-9. doi: 10.1074/jbc.M109.098699.