Animal models of inflammatory diseases and tissue remodelling
Our laboratory researches key nodes in signalling networks involved in prevalent age-associated pathologies, such as metabolic/cardiovascular diseases and cancer. GRK2 kinase is one of these critical signalling centres. The main role of GRK2 is regulation, along with arrests, of multiple G protein-coupled receptors (GPCR) mediating signalling, a family of hundreds of membrane proteins of key physiological and pharmacological importance. Moreover, we and other groups have shown that GRK2 can also affect cell signalling networks by interfacing directly and/or phosphorylating non-GPRC components of biochemical cascades (such as HDAC6, IRS1, PI3K, EPAC, Mdm2, Smads or p38 Mapk). Our group has determined that some of these integrated interactions underlie GRK2’s involvement in the control of cell migration, angiogenesis or insulin resistance (IR).
Relevantly, GRK2 levels/activity are altered in human pathologies such as cancer, inflammation, and IR-related metabolic/cardiovascular diseases. We are seeking to understand the mechanisms that lead to altered expression of GRK2 in these clinical situations, how concurrent changes in GRK2 levels (involving different tissues and cell types) are integrated at a cell and organism level, and how they can encourage disease progression; using cell and animal models (including homozygous, conditional, or tissue-specific GRK2 deficient animals), as well as patient samples or animal models of disease. This is critical in determining the viability of GRK2 as a diagnostic biomarker and/or useful therapeutic target.
The group pursues three main lines of research:
- Researching how changes in GRK2 expression in different cell types in a specific tumour (tumoral, macrophages and endothelial cells) may act in a synergistic way to promote different aspects of tumour progression (proliferation, survival, angiogenesis, metastatic invasion) by modulating GPCRs or HDAC6-controlled networks, among others.
- Analysing the GRK2 node as a central integrator of biochemical cascades relevant for IR-related pathologies and co-morbidities in different tissues and cell types (adipose, liver, pancreas, heart, macrophages/immune cells), simultaneously modulating the insulin cascade and key GPCRs for the control of metabolic homeostasis, nutrient perception or insulin secretion/sensitivity, as well as other signalling proteins that interact with GRK2 related to IR conditions (such as EPAC, eNOS or p38 Mapk).
- Exploring the functional implications of Gαq interactome. We have discovered new Gαq interactions with PB1 domains such as PKCζ, and we are investigating the functional impact of this new Gαq interactome on cell death, autophagy and oxidative stress processes, and on the development of cardiovascular disease.
Federico Mayor Menéndez
Universidad Autónoma de Madrid-Molecular Biology Institute
| Other team members:
Mayor Menéndez, Federico. CIBER-CV. CB16/11/00278. ISCIII. 2017-2021.
Mayor Menéndez, Federico / Murga Montesinos, Cristina. GRK2 as an integrator signalling node in pathophysiological situations. SAF2017-84125-R. MINECO. 2017-2020.
Mayor Menéndez, Federico. Novel molecular mechanisms linking GRK2 as a new therapeutic target in diabetes. EFSD: European Foundation for the study of Diabetes. 2014-2016.
Mayor Menéndez, Federico. RECAVA: Cardiovascular Research Network. RD12/0042/0012. ISCIII. 2013-2016.
Mayor Menéndez, Federico. INDISNET: Molecular and cellular networks in inflammatory disease. S2010/BMD-2332. CAM. 2012-2015.
Mayor Menéndez, Federico. ONCORNET: Oncogenic receptor network of excellence and training. 641833. European Commission. 2015-2019.
Ribas Núñez, Catalina. New functional complexes resulting from Gαq interface with proteins that contain PB1 domains and the possible repercussion in cardiovascular disease. PI14/00201. ISCIII. 2015-2017.
Mayor Menéndez, Federico. Physiological integration and pathological implications of functional GRK2 interactions in different cell types and contexts. SAF2014-55511-R. MINECO. 2015-2017.
Ribas Núñez, Catalina. New functional complexes resulting from Gαq interface with proteins that contain PB1 domains and the possible repercussion in cardiovascular disease. Fundación Ramón Areces. 2015-2018.
Ribas Núñez, Catalina. Un nuevo interactoma de Gq implicado en la modulación de autofagia y estrés oxidativo: repercusión en disfunción endotelial y patalogías relacionadas. PI18/01662. ISCIII. 2019-2021.
Caracterizar la repercusión de las interacciones Gq implicadas en muerte celular, autofagia y estrés oxidativo en diferentes modelos celulares endoteliales.
This grant is funded by the 2017-2020 Spanish Science, Technology and Innovation Research Plan and the ISCIII – Subdirectorate General for Evaluation and Promotion of Research – and co-financed by the European Regional Development Fund, Operational Programme Smart Growth 2014-2020 according to Regulation (EU) no. 1303/2013.
Penela P, Nogués L, Mayor F. Role of G protein-coupled receptor kinases in cell migration. Curr. Opin. Cell Biol. 2014. 27: 10-17. FI: 8.467(Q1). PMID: 24680425. DOI: 10.1016/j.ceb.2013.10.005.
Rivas V, Carmona R, Muñoz-Chápuli R, Mendiola M, Nogués L, Reglero C, Miguel-Martín M, García-Escudero R, Dorn GW, Hardisson D, Mayor F, Penela P. Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J. Clin. Invest. 2013. 123: 4714-4730. FI: 13.765(Q1). PMID: 24135140. DOI: 10.1172/JCI67333.
Lafarga, Vanesa, Aymerich, Ivette, Tapia, Olga, Mayor, Jr., Federico, Penela, Petronila. A novel GRK2/HDAC6 interaction modulates cell spreading and motility. EMBO J 2012. 31: 856-869. FI: 9.822(Q1). PMID: 22193721. DOI: 10.1038/emboj.2011.466.
Garcia-Guerra L, Nieto-Vazquez I, Vila-Bedmar R, Jurado-Pueyo M, Zalba G, Díez J, Murga C, Fernández-Veledo S, Mayor F, Lorenzo M. G Protein-Coupled Receptor Kinase 2 Plays a Relevant Role in Insulin Resistance and Obesity. DIABETES 2010. 59: 2407-2417. FI: 8.889(Q1). PMID: 20627936. DOI: 10.2337/db10-0771.
Penela P, Rivas V, Salcedo A, Mayor F. G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc Natl Acad Sci U S A 2010. 107: 1118-1123. FI: 9.771(Q1). PMID: 20080565. DOI: 10.1073/pnas.0905778107.