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 and (v) developing tools to specifically target them. We are 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, culture cells and model organisms (yeast, frog embryos) for functional studies and synthetic biology tools to manipulate and monitor signaling with exquisite spatiotemporal resolution.
Alex Luebbers – Graduate student
– Postdoctoral Associate
Marcin Maziarz– Postdoctoral Associate
Jong-Chan (JC) Park– Postdoctoral Associate
Jingyi Zhao– Postdoctoral Associate
Jessica Chen- Undergraduate Student
Cairo de Souza- Undergraduate Student
Zhiming (Charlie) Zhao- Undergraduate Student
Postdoctoral positions available. Check here.
- Marivin A, Morozova V, Walawalkar I, Leyme A, Kretov DA, Cifuentes D, Dominguez I, Garcia-Marcos M. GPCR-independent activation of G proteins promotes apical cell constriction in vivo. Journal of Cell Biology. 2019; May 6;218(5):1743-1763. PMID: 30948426.
- Maziarz M, Leyme A, Marivin A, Luebbers A, Patel PP, Chen Z, Sprang SR, Garcia-Marcos M. Atypical activation of Gαq by the oncogenic mutation Q209P. Journal of Biological Chemistry. 2018; Oct 23. PMID: 30352874
- Maziarz M, Broselid S, DiGiacomo V, Park JC, Luebbers A, Garcia-Navarrete L, Blanco-Canosa JB, Baillie GS, Garcia-Marcos M. A biochemical and genetic discovery pipeline identifies PLCδ4b as a non-receptor activator of heterotrimeric G proteins. Journal of Biological Chemistry. 2018; Sep 7. PMID: 30194280.
- Leyme A, Marivin A, Maziarz M, DiGiacomo V, Papakonstantinou MP, Patel PP, Blanco-Canosa JB, Walawalkar I, Rodriguez-Davila G, Dominguez I, Garcia-Marcos M. Specific inhibition of GPCR-independent signaling by a rationally engineered protein. Proceedings of the National Academy of Sciences. 2017 Nov 28;114(48):E10319-E10328. PMID: 29133411
- 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 Gαi activation by non-GPCR proteins with a Gα-Binding and Activating motif. Nature Communications. May 18;8:15163. PMID: 28516903
- Marivin A., Leyme A., Parag-Sharma K., DiGiacomo V., Cheung A.Y., Nguyen L.T., Dominguez I. Garcia-Marcos M. Dominant negative Gα subunits as a novel mechanism of trimeric G protein signaling dysregulation in human disease. Science Signaling. Apr 12;9(423):ra37. PMID: 27072656.
- Coleman BD, Marivin A, Parag-Sharma K, DiGiacomo V, Kim S, Pepper JS, Casler J, Nguyen LT, Koelle MR, Garcia-Marcos M. Evolutionary conservation of a GPCR-independent mechanism of trimeric G protein activation. Molecular Biology and Evolution. 2016 Mar;33(3):820-37. PMID: 26659249
- Leyme A, Marivin A, Perez-Gutierrez L, Nguyen LT, Garcia-Marcos M. Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin. Journal of Cell Biology. 2015 Sep 28;210(7):1165-84. PMID: 26391662.
- Aznar N, Midde KK, Dunkel Y, Lopez-Sanchez I, Pavlova Y, Marivin A, Barbazán J, Murray F, Nitsche U, Janssen KP, Willert K, Goel A, Abal M, Garcia-Marcos M, Ghosh P. Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. Elife. 2015 Jun 30;4:e07091. PMID: 26126266
- Ghosh P, Garcia-Marcos M. Do All Roads Lead to Rome in G-Protein Activation? Trends in Biochemical Sciences. 2019 Nov 18. pii: S0968-0004(19)30211-7. PMID: 31753703
- DiGiacomo V, Marivin A, Garcia-Marcos M. When Heterotrimeric G Proteins Are Not Activated by G Protein-Coupled Receptors: Structural Insights and Evolutionary Conservation. 2018; Jan 23; 57(3):255-257. PMID: 29035513.
- Garcia-Marcos M., Ghosh P., Farquhar M.G. GIV/ Girdin transmits signals from multiple receptors by triggering trimeric G protein activation. Journal of Biological Chemistry. 2015. Mar 13;290(11):6697-704. PMID: 25605737.
Complete list can be found at BU Profiles