Overview of our accomplishments:
Environmental cues are transmitted to the interior of the cell via a complex network of signaling hubs. Heterotrimeric G proteins are one such major signaling hub in eukaryotes. Over the years, our group has systematically pursued in depth the mechanism and biological implications of an intracellular heterotrimeric GTPase system, and revealed along the way how G protein signaling via a novel family of multi-modular scaffolds, i.e., Guanine nucleotide exchange modulators (GEMs) is fundamentally distinct from the conventional G protein signaling from the cell surface by G protein-coupled receptors (GPCRs).
Our contributions to this emerging field can be categorized into the following 4 related areas:
1. Identification and characterization of novel guanine-nucleotide exchange modulators of heterotrimeric G proteins, called GEMs: We were one of the original discoverer of this fundamental signaling system beginning with the discovery of GIV-GEM [in 2009] and extending to other class members such as Daple-GEM [in 2015]. We have shown the central importance of the GEM system in regulating a variety of cellular processes, including cell motility, survival, protein processing, maintaining tight junctions, and in endocytic, secretory and exocytic functions. They have revealed the mechanistic basis of function of this system via phosphorylation, protein:protein interactions and systems and structural biology studies.
2. Defining a new paradigm for transactivation of G-proteins by multiple classes of single transmembrane receptors, making them essentially G protein-coupled receptors: Canonical signal transduction via heterotrimeric G-proteins is spatially and temporally restricted; it is triggered exclusively by GPCRs at the plasma membrane (PM) and is terminated within a few hundred milliseconds. We were the first to show that GEMs coordinate cellular responses to a variety of environmental signals by using G proteins to modulate signals initiated by diverse classes of receptors, thereby allowing non-GPCRs to engage with and modulate G-proteins. More importantly, GEMs coordinate cellular responses by being able to modulate G proteins at the plasma membrane as well as on internal organelles. In doing so, we defined for the first time how GEM-dependent G protein signaling breaks all known 'rules' of G protein signaling that is triggered by GPCRs because of their unique ability as signal integrators and unusual temporal and spatial features.
3. Impact of GEMs on Modern Medicine: Our work, based on careful studies that incorporate cutting edge cell, molecular and structural biology showed that alterations in this system are clearly important in human diseases, and provided impetus to drug development to target the GEM system in disease states. My clinical training and knowledge of medicine makes us uniquely qualified to seamlessly translate our discoveries from bench-to-bedside, whichever direction our findings take us. Although the G-protein/GPCR and tyrosine-based signaling pathways remain the core targets of modern medicine, it is expected that our contributions revealing GEM-mediated G protein signaling are likely to reveal unforeseen new avenues for understanding, diagnosing and alleviating human suffering.
4. Technology Development to Monitor or Target GEM-driven Diseases: While exploring the role of G-proteins as critical regulators of signal transmission downstream of unusual receptors, we have demonstrated the diagnostic and therapeutic potential of key signaling interfaces in diverse pathophysiologic states including diabetes, organ fibrosis, and cancer. Ongoing studies should reveal the further importance of this pathway in settings such as HIV infection, aging, infertility, schizophrenia, Alzheimers and others. Several of these discoveries have led to patents.
How we make discoveries:
in a variety of model systems...
- Standard protein chemistry
- Standard molecular biology
Computational chemistry (collaborative)
- Electron microscopy and Immuno-EM
- Live-cell imaging
to understand the pathogenesis of, and discover therapeutic targets in...
- Mammalian cells in 2D and 3D cultures, organoids
- Rodents (mice)
- Colorectal cancer
- Breast cancer
- Aging, inflammation, metabolism
- Renal Injury (nephrotic syndrome, acute tubular nectrosis)
- Liver Injury/inflammation/cirrhosis/HCCa
- Neuronal signaling, pain & addiction
- Alzheimers, Parkinson's, and Schizophrenia,
- Type II DM/Insulin Resistance