Silvio Conte Building, K-208
72 E. Concord Street
Boston, MA 02118
Lab Phone: 617-638-4037
Ph.D. Biochemistry, University of the Basque Country/ Universite Libre de Bruxelles
|Vincent di Giacomo
|Kshitij (Kay) Sharma
Positions available: We are constantly looking for talented graduate students and postdocs. Interested candidates should send a resume/CV and a short statement describing experience, goals and reasons for the interest in the lab to Dr. Garcia-Marcos. (email@example.com)
G PROTEIN SIGNALING CIRCUITS IN THE MOLECULAR BASIS OF DISEASE
Our lab uses a multidisciplinary approach to identify and characterize new key players in signal transduction with the ultimate goal of further the understanding of the molecular basis of disease and develop novel therapeutic approaches. The scope of our work ranges from studies of the structural basis of molecular interactions to analyses at the organismal level. We put a strong emphasis on studying the role of signal transduction in controlling cell biological processes.
Our laboratory is specifically interested in signal transduction via trimeric G proteins and how its dysregulation underlies the molecular basis of disease. Trimeric G proteins are critical signal transducing molecules found all the way from simple unicellular organisms to humans. Their classical mechanism of activation is mediated by the action of G protein-coupled receptor (GPCR), transmembrane proteins that sense extracellular signals and relay them to G proteins inside the cell. This signaling mechanism regulates essentially any human physiological function and more than >30% of the drugs in the market target some type of GPCR.
We are exploring and expanding novel signaling mechanisms via trimeric G proteins. We are focused on the identification and characterization of a new class of activators of trimeric G proteins, as well as on their possible targeting for therapeutic purposes. Like GPCRs, these activators are Guanine nucleotide Exchange factors (GEFs), but instead of membrane receptors they are cytoplasmic factors. We and others have found that some of these nonreceptor GEFs “rewire” signal transduction in different pathological settings, including cancer, fibrosis, insulin resistance and kidney failure, among many others.
We are currently carrying out exciting research on several areas related to this general topic. We are studying the role of previously characterized nonreceptor GEFs in cancer cell biology processes associated with metastasis and neurodevelopmental alterations linked to neonatal brain defects. In parallel, we are identifying and characterizing new nonreceptor GEFs, which is taking us into new and exciting research areas like the modulation of neurotransmission. Simultaneously, we are screening and characterizing small molecules to modulate these signaling mechanisms. For all this, we use a variety of experimental models (mammalian cells, yeast, frog embryos) and techniques, which range from in vitro biochemistry to developing synthetic biology tools that allow us to manipulate and monitor signaling events with exquisite spatiotemporal resolution.
- Leyme, A., Marivin, A., Perez-Gutierrez, L., Nguyen, L. T., and Garcia-Marcos, M. (2015) Integrins activate trimeric G proteins via the non-receptor protein GIV/ Girdin. J Cell Biol In press
- 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. PubMed
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. PubMed
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. PubMed
Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin. Lin C, Ear J, Midde K, Lopez-Sanchez I, Aznar N, Garcia-Marcos M, Kufareva I, Abagyan R, Ghosh P. Mol Biol Cell. 2014 Sep 3. pii: mbc.E14-05-0978. [Epub ahead of print]
- Hsp70-bag3 interactions regulate cancer-related signaling networks. 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. Cancer Res. 2014 Sep 1;74(17):4731-40.
- Different Biochemical Properties Explain Why Two Equivalent Gα-subunit Mutants Cause Unrelated Diseases. Leyme A, Marivin A, Casler J, Nguyen LT, Garcia-Marcos M. J Biol Chem. 2014
- Protein kinase C-theta (PKCθ) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin. López-Sánchez I, Garcia-Marcos M, Mittal Y, Aznar N, Farquhar MG, Ghosh P. Proc Natl Acad Sci U S A. Apr 2;110(14):5510-5. 2013.
- Gαs promotes EEA1 endosome maturation and shuts down proliferative signaling through interaction with GIV (Girdin). Beas AO, Taupin V, Teodorof C, Nguyen LT, Garcia-Marcos M, Farquhar MG. Mol Biol Cell. 2012 Dec;23(23):4623-34. doi: 10.1091/mbc.E12-02-0133.
- García-Marcos M., Kietrsunthorn, P., Pavlova, Y., Adia M., Ghosh P., Farquhar MG. Functional characterization of the guanine nucleotide exchange factor (GEF) motif of GIV protein reveals a threshold effect in signaling. Proceedings of the National Academy of Sciences. 2012, 106(6): 1961-6. PMID: 22308453.
- Mittal Y., Pavlova Y, Garcia-Marcos M. and Ghosh P. Src homology domain 2-containing protein-tyrosine phosphatase-1 (SHP-1) binds and dephosphorylates G(alpha)-interacting, vesicle-associated protein (GIV)/Girdin and attenuates the GIV-phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. Journal of Biological Chemistry. 2011. 286(37):32404-15.
- Lin., C., Ear, J., Pavlova, Y., Kufareva, I., Abagyan, R., Ghassemian, M., Garcia-Marcos, M., and Ghosh, P. Tyrosine phosphorylation of the Gα-interacting protein GIV promotes activation of phosphoinositide 3-kinase during cell migration. Science Signaling. 2011. 4(192):ra64.
- García-Marcos M., Kietrsunthorn, P., Wang H, Ghosh P., Farquhar MG G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs. Journal of Biological Chemistry. 2011. 286(32):28138-49.
- Ghosh, P., Garcia-Marcos, M., Farquhar, M.G. To Grow or Go: A GIV/Girdin rheostat tunes switch-like signaling to control tumor progression, Cell Adhesion and Migration, 2011. 5(3). Review.
- Garcia-Marcos, M., Ghosh, P, and Farquhar, MG. Molecular Basis of a Novel Oncogenic Mutation in GNAO1. Oncogene, 2011. 30(23): 2691-96.
- Garcia-Marcos M., Ear, J., Farquhar, M. and Ghosh P. A GEF and a GDI Regulate Autophagy by Balancing G protein Activity and Growth Factor Signals. Molecular Biology of the Cell, 2011. 22(5): 673-686.
- Garcia-Marcos M., Jung BH., Forry EP., Johannson C., Cabrera BL., Carethers JM., Ghosh P. Expression of GIV/Girdin, a metastasis-related protein, predicts cancer survival in colon cancer patients. FASEB J, 2011. 25(2):590-9
- Ghosh P., Beas A., Bornheimer SJ., Garcia-Marcos M., Ear, J., Carethers JM., Jung BH., Cabrera BL., Farquhar MG. A Gαi-GIV molecular complex binds EGF receptor and decides whether cells migrate or proliferate in response to growth factors. Molecular Biology of the Cell, 2010. 21(13):2338-54.
- García-Marcos M., Ghosh P., Ear J., Farquhar MG. A novel structural determinant that renders Gαi sensitive to activation by GIV/Girdin is required to promote cell migration. Journal of Biological Chemistry. 2010. 285(17):12765-77.
- García-Marcos M., Ghosh P., Farquhar MG. GIV/ Girdin is a non-receptor GEF for Galphai with a unique motif that regulates Akt activation. Proceedings of the National Academy of Sciences, 2009. 106(9):3178-83.
- Ghosh P., García-Marcos M., Bornheimer SJ., Farquhar MG. Activation of Gαi3 triggers cell migration through regulation of GIV. Journal of Cell Biology, 2008. 182(2):381-93.