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
Postdoctoral Training: University of California, San Diego
|Lien (Ashley) Nguyen
|Kshitij (Kay) Sharma
We are seeking highly motivated candidates with a recent PhD and a strong background in Biochemistry, Molecular and Cellular Biology as well as an extensive knowledge of signal transduction. The candidate must have a strong commitment to science and be able to work under pressure in a fast paced and very demanding research environment.
The ideal candidate should have demonstrated experience in most of the following techniques: tissue culture of mammalian cells, fluorescence microscopy, molecular cloning, immunoblotting, immunoprecipitation, radioisotope-based assays and protein purification. Additional experience with one or several of the following techniques will be positively evaluated: high throughput small molecule screening, yeast two-hybrid genetic screening, structural biology (X-ray crystallography). Ability to work as a team player, good communication skills, and strong commitment to science are expected.
G PROTEIN SIGNALING CIRCUITS IN THE MOLECULAR BASIS OF DISEASE
A major goal of cell biology is to understand how cells respond to changes in their environment through a mechanism known as signal transduction. Dysregulation of this process is intimately related to the development of many diseases such as cancer, cardiovascular disease, inflammation, diabetes, etc. Our laboratory is interested in investigating how signaling via trimeric G proteins controls cell behavior in health and disease.
Trimeric G proteins are gate-keepers of signal transduction that regulate virtually any physiological process and dysregulation of their function is the cause of many diseases. The biomedical importance and impact in public health of this signaling mechanism is made most notorious by the fact that more than 25% of the marketed drugs target it. Although this is a well established signal transduction mechanism, recent discoveries have uncovered an increased complexity in the G protein regulatory network. It has become clear that in addition to G protein coupled receptors (GPCRs) other accessory proteins (e.g., GAPs and GDIs) also control G protein activity and function. These accessory proteins contribute to the assembly of alternative or complementary signaling circuits that shape cellular responses.
We have contributed to the characterization of a new type of “atypical” G protein regulators called non-receptor GEFs, which mimic the action exerted by GPCRs but are not membrane receptors. We recently demonstrated that GIV (a.k.a. Girdin) is the first non-receptor GEF that works via a defined motif and found that it controls cell migration, mitosis and autophagy. We also identified a critical role of GIV’s GEF function in the development of human disease as its abnormal upregulation in tumor cells promotes cancer metastasis, the cause of 95% of cancer-related deaths. Importantly, the survival rate for patients with GIV-positive tumors is dramatically reduced compared to the patients with GIV-negative tumors. Thus, GIV has emerged as novel G protein regulator with a critical role in cancer.
Our overall hypothesis
is that GIV is the first member of a larger family of novel G protein regulators that control cellular behavior by virtue of coupling to G proteins via a signature GEF motif. We propose that the interplay between members of this new family of proteins and other components of the G protein regulatory machinery represents a new paradigm differing from the canonical view of trimeric G proteins and that dysregulation of this novel mechanism of signal transduction can give rise to different diseases. In addition, disruption of the GEF motif-G protein interface may be exploited as a therapeutic target in diseased states triggered by enhancement of the GEF function, as it occurs for GIV during cancer metastasis.
- To identify and characterize members of a new family of G protein regulators that share a common GEF motif.
- To investigate how the interplay between these new regulators and other signaling proteins establishes non-canonical signaling circuits to control cell behavior.
- To dissect the structural determinants required to assemble the GEF-G protein interface and to identify molecular probes for the therapeutic targeting of this interface.
- 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.