Mikel Garcia-Marcos

Current Research

Research in the Garcia-Marcos Lab aims to understand the mechanisms and consequences cell communication via heterotrimeric G-proteins (Gαβγ) because they represent major intracellular hubs of signaling with very direct biomedical relevance. The established dogma is that these G-proteins are activated by G-protein coupled receptors (GPCR) present at the surface of eukaryotic cells. GPCRs are the largest family of druggable targets in the human genome. From a biological standpoint, they mediate a large fraction of all transmembrane signaling in our body, including responses triggered by every major neurotransmitter and by two-thirds of hormones. Biomedically, they stand out as prominent pharmacological targets for many diseases, with an estimated market value of hundreds of billions of dollars per year.

Despite the clear importance of GPCR and the G-proteins they activate in biology and biomedicine, there is a large gap in knowledge about alternative and complementary mechanism by which G-proteins are regulated. Our laboratory is recognized for leading efforts in the discovery and characterization of new components of the G-protein regulatory network that exert a profound impact of cellular communication in health and disease. Our ongoing work has direct implications in cancer, embryonic development defects, and neurological disorders.

To achieve our goals, we use a multi-scale approach, in which we integrate information from interrogating signaling at the molecular, cellular, and organismal level. For this, biochemistry, cell biology, and genetics are combined in various experimental systems, from purified proteins, to cultured cells, to different model organisms (mice, frogs, zebrafish). We also have interest in the development of novel tools, like optical biosensors to detect signaling activity in cells, or chemogenetic/optogenetic tools, which use bioinert chemicals or light to trigger cell responses on demand.

Selected Publications

• Janicot R., M. Maziarz, J.C. Park, J. Zhao, A. Luebbers, E. Green, C.E. Philibert, H. Zhang, M.D. Layne, J.C. Wu, and M. Garcia-Marcos (2024). Direct interrogation of context-dependent GPCR activity with a universal biosensor platform. Cell 24:00065-5.
• Zhao J., V. DiGiacomo, M. Ferreras-Gutierrez, S. Dastjerdi, A.I. de Opakua, J.C. Park, A. Luebbers, Q. Chen, A. Beeler, F.J. Blanco, and M. Garcia-Marcos (2023). Small-molecule targeting of GPCR-independent non-canonical G protein signaling in cancer. Proceedings of the National Academy of Sciences 120:e2213140120.
• Park J.C., A. Luebbers, M. Dao, A. Semeano, A.M. Nguyen, M.P. Papakonstantinou, S. Broselid, H. Yano, K.A. Martemyanov, and M. Garcia-Marcos (2023). Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G-protein subunits. Molecular Cell 23:00428-8. 
• Marivin A., R.X. Ho, and M. Garcia-Marcos (2022). DAPLE orchestrates apical actomyosin assembly from junctional polarity complexes. J Cell Biol 221:e202111002.
• Garcia-Marcos M. (2021). Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators. eLife 10:e65620.
• Garcia-Marcos M., K. Parag-Sharma, A. Marivin, M. Maziarz, A. Luebbers, and L.T. Nguyen (2020). Optogenetic activation of heterotrimeric G-proteins by LOV2GIVe, a rationally engineered modular protein. Elife 9:e60155.
• Maziarz M., J.C. Park, A. Leyme, A. Marivin, A. Garcia-Lopez, P.P. Patel, and M. Garcia-Marcos (2020). Revealing the Activity of Trimeric G-proteins in Live Cells with a Versatile Biosensor Design. Cell 182:770-785.
• DiGiacomo V., M. Maziarz, A. Luebbers, J.M. Norris, P. Laksono, and M. Garcia-Marcos (2020). Probing the mutational landscape of regulators of G Protein signaling proteins in cancer. Science Signaling 13:eaax8620.

Courses Taught:

• MB 721 Graduate Biochemistry