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.
Vincent di Giacomo – Postdoctoral Associate
Anthony Leyme – Postdoctoral Associate
Arthur Marivin – Postdoctoral Associate
Anthony Cheung – Undergraduate Student
Jillian Norris – Undergraduate Student
Prachi Patel – Undergraduate Student
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.
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.
Leyme A, Marivin A, Garcia-Marcos M. GIV/Girdin (Ga-interacting, Vesicle-associated Protein/Girdin) Creates a Positive Feedback Loop That Potentiates Outside-in Integrin Signaling in Cancer Cells. J Biol Chem. 2016 Apr 8; 291(15):8269-82. PMID: 26887938.
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.
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.
Bhandari D, Lopez-Sanchez I, To A, Lo IC, Aznar N, Leyme A, Gupta V, Niesman I, Maddox AL, Garcia-Marcos M, Farquhar MG, Ghosh P. Cyclin-dependent kinase 5 activates guanine nucleotide exchange factor GIV/Girdin to orchestrate migration-proliferation dichotomy. Proc Natl Acad Sci U S A. 2015 Sep 1; 112(35):E4874-83. PMID: 26286990.
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; 4:e07091. PMID: 26126266.
Garcia-Marcos M, Ghosh P, Farquhar MG. GIV/Girdin transmits signals from multiple receptors by triggering trimeric G protein activation. J Biol Chem. 2015 Mar 13; 290(11):6697-704. PMID: 25605737.
Lin C, Ear J, Midde K, Lopez-Sanchez I, Aznar N, Garcia-Marcos M, Kufareva I, Abagyan R, Ghosh P. Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin. Mol Biol Cell. 2014 Nov 5; 25(22):3654-71. PMID: 25187647.
Colvin TA, Gabai VL, Gong J, Calderwood SK, Li H, Gummuluru S, Matchuk ON, Smirnova SG, Orlova NV, Zamulaeva IA, Garcia-Marcos M, Li X, Young ZT, Rauch JN, Gestwicki JE, Takayama S, Sherman MY. Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Res. 2014 Sep 1; 74(17):4731-40. PMID: 24994713.
Complete list can be found at BU Profiles