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
Malav Dave- Undergraduate Student
Cairo de Souza- Undergraduate Student
Zhiming (Charlie) Zhao- Undergraduate Student
Postdoctoral positions available. Check here.
Maziarz M, Leyme A, Marivin A, Luebbers A, Patel PP, Chen Z, Sprang SR, Garcia-Marcos M. Atypical activation of Gaq by the oncogenic mutation Q209P. J Biol Chem. 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 PLCd4b as a non-receptor activator of heterotrimeric G proteins. J Biol Chem. 2018 Sep 07. PMID: 30194280.
Martemyanov KA, Garcia-Marcos M. Making useful gadgets with miniaturized G proteins. J Biol Chem. 2018 May 11; 293(19):7474-7475. PMID: 29752421.
- 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 PMCID: PMC5715746
- 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.
- 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. Nat Commun. 2017 May 18;8:15163. doi: 10.1038/ncomms15163. PMID: 28516903. View in: PubMed
- 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 Nov 18. PMID: 27864364. View in: PubMed
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; 9(423):ra37. PMID: 27072656.
View in: PubMed
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. Mol Biol Evol. 2016 Mar; 33(3):820-37. PMID: 26659249.
View in: PubMed
Leyme A, Marivin A, Perez-Gutierrez L, Nguyen LT, Garcia-Marcos M. Integrins activate trimeric G proteins via the nonreceptor protein GIV/Girdin. J Cell Biol. 2015 Sep 28; 210(7):1165-84. PMID: 26391662.
View in: PubMed
Complete list can be found at BU Profiles