We investigate signal transduction mechanisms with the ultimate goal of elucidating the molecular basis of human diseases and developing novel therapeutic approaches.
Our main interest is in heterotrimeric G proteins, which are molecular switches that relay extracellular signals. Heterotrimeric G proteins are primarily activated by G protein-coupled receptors (GPCRs) located at the plasma membrane. However, our lab focuses on a group of cytoplasmic factors that mimic the action of GPCRs by directly activating heterotrimeric G proteins. These non-receptor activators “rewire” signal transduction in different pathological settings, including cancer, fibrosis, insulin resistance and kidney failure, among many others.
Our current efforts are focused on:
(i) identifying the members of this group of non-receptor activators
(ii) defining their role in normal and pathological scenarios
(iii) characterizing the molecular mechanisms by which they are regulated
(iv) understanding the structural basis for their action on G proteins
(v) developing tools to specifically target them.
We are currently exploring this unconventional aspect of G protein signaling in the context of cancer, embryonic development and neurotransmission.Our multidisciplinary approach includes in vitro biochemistry to characterize protein complexes, cultured cells and model organisms (yeast, frog embryos, fish) for functional studies, and synthetic biology tools to manipulate and monitor signaling with exquisite spatiotemporal resolution..
- University of the Basque Country, PhD
- University of the Basque Country, BS
- Published on 11/13/2017
Leyme A, Marivin A, Maziarz M, DiGiacomo V, Papakonstantinou MP, Patel PP, Blanco-Canosa JB, Walawalkar IA, Rodriguez-Davila G, Dominguez I, Garcia-Marcos M. Specific inhibition of GPCR-independent G protein signaling by a rationally engineered protein. Proc Natl Acad Sci U S A. 2017 Nov 28; 114(48):E10319-E10328. PMID: 29133411.
- Published on 10/16/2017
DiGiacomo V, Marivin A, Garcia-Marcos M. When Heterotrimeric G Proteins Are Not Activated by G Protein-Coupled Receptors: Structural Insights and Evolutionary Conservation. Biochemistry. 2018 Jan 23; 57(3):255-257. PMID: 29035513.
- Published on 9/12/2017
Maziarz M, Garcia-Marcos M. Rapid kinetic BRET measurements to monitor G protein activation by GPCR and non-GPCR proteins. Methods Cell Biol. 2017; 142:145-157. PMID: 28964333.
- Published on 9/11/2017
Maziarz M, Garcia-Marcos M. Fluorescence polarization assays to measure interactions between Ga subunits of heterotrimeric G proteins and regulatory motifs. Methods Cell Biol. 2017; 142:133-143. PMID: 28964332.
- Published on 8/17/2017
DiGiacomo V, de Opakua AI, Papakonstantinou MP, Nguyen LT, Merino N, Blanco-Canosa JB, Blanco FJ, Garcia-Marcos M. The Gai-GIV binding interface is a druggable protein-protein interaction. Sci Rep. 2017 Aug 17; 7(1):8575. PMID: 28819150.
- Published on 5/18/2017
de Opakua AI, Parag-Sharma K, DiGiacomo V, Merino N, Leyme A, Marivin A, Villate M, Nguyen LT, de la Cruz-Morcillo MA, Blanco-Canosa JB, Ramachandran S, Baillie GS, Cerione RA, Blanco FJ, Garcia-Marcos M. Molecular mechanism of Gai activation by non-GPCR proteins with a Ga-Binding and Activating motif. Nat Commun. 2017 May 18; 8:15163. PMID: 28516903.
- Published on 11/18/2016
Parag-Sharma K, Leyme A, DiGiacomo V, Marivin A, Broselid S, Garcia-Marcos M. Membrane Recruitment of the Non-receptor Protein GIV/Girdin (Ga-interacting, Vesicle-associated Protein/Girdin) Is Sufficient for Activating Heterotrimeric G Protein Signaling. J Biol Chem. 2016 Dec 30; 291(53):27098-27111. PMID: 27864364.
- Published on 9/12/2016
Gupta V, Bhandari D, Leyme A, Aznar N, Midde KK, Lo IC, Ear J, Niesman I, López-Sánchez I, Blanco-Canosa JB, von Zastrow M, Garcia-Marcos M, Farquhar MG, Ghosh P. GIV/Girdin activates Gai and inhibits Gas via the same motif. Proc Natl Acad Sci U S A. 2016 09 27; 113(39):E5721-30. PMID: 27621449.
- Published on 4/12/2016
Garcia-Marcos M, VanHook AM. Science Signaling Podcast for 12 April 2016: G proteins in auriculo-condylar syndrome. Sci Signal. 2016; 9(423):pc9. PMID: 27072654.
- Published on 4/12/2016
Marivin A, Leyme A, Parag-Sharma K, DiGiacomo V, Cheung AY, Nguyen LT, Dominguez I, Garcia-Marcos M. Dominant-negative Ga subunits are a mechanism of dysregulated heterotrimeric G protein signaling in human disease. Sci Signal. 2016 Apr 12; 9(423):ra37. PMID: 27072656.
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