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Research Interests: 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.
Our current goals can be summarized as follows:
1)To identify and characterize members of a new family of G protein regulators that share a common GEF motif.
2)To investigate how the interplay between these new regulators and other signaling proteins establishes non-canonical signaling circuits to control cell behavior.
3)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.
Research Interests
Papers共 129 篇Author StatisticsCo-AuthorSimilar Experts
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bioRxiv the preprint server for biology (2024)
The Journal of biological chemistryno. 3 (2024): 105756-105756
Molecular pharmacology (2024)
ASPET 2024 Annual Meeting Abstract - Cellular and Molecular Pharmacology (2024)
Remi Janicot,Marcin Maziarz,Jong -Chan Park,Jingyi Zhao,Alex Luebbers, Elena Green, Clementine Eva Philibert,Hao Zhang, Mathew D. Layne,Joseph C. Wu,Mikel Garcia-Marcos
CELLno. 6 (2024): 1527-1546.e25
Structure (London, England : 1993)no. 5 (2023): 505-506
crossref(2023)
Proceedings of the National Academy of Sciences of the United States of Americano. 18 (2023)
Journal of Biological Chemistryno. 3 (2023): 104387-104387
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