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Ghosh Lab Research

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

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. 

Ongoing projects in the laboratory include:

  • A comprehensive analysis of the phosphoproteome of G proteins by growth factors
  • Compartmentalization of G protein signaling by growth factors (a comprehensive assessment of impact on GPCRs and Ric8A/B).
  • Decoding the invariant allosteric path to bring about a nucleotide 'fumble' in the trimeric GTPase Gi.
  • Structural basis for modulation (inhibition as a GDI) of the oncoprotein GNAS by GEMs
  • Cell permeant peptides as surrogates to modulate G proteins in cells (Collaborative with Professor Diana Imhof, Germany).

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.

Receptors/Sensors currently being studied in our laboratory include: 

  • Growth factor RTKs:
    • EGFR
    • Her2
  •  GPCRs:
    • CXCR4
    • Adiponectin
    • Multiple IBD-associated receptors (including orphan GPCRs)
  • Cytokine, immune checkpoint and pathogen sensors:
    • TLR4
    • NOD2
    • IL17RA
    • PDCD1 (PD1)

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.

Diseases currently being studied in our laboratory include:

  • Bacterial Infections:
    • Sepsis
    • Colitis
    • Fundamental biology investigating pathogen sensors (NOD2, TLRs).
    • Multi-omic approach to decoding innate immune responses (Macrophage and Neutrophils)
    • The impact of gender on innate immune responses
  • Immunometabolism:
    • Obesity and Insulin resistance
    • Atherosclerosis
    • Circadian Rhythm
    • Non-alcoholic steato hepatitis
  • Cancer Biology [breast, lung, colon, gastric, esophageal, pancreas, biliary]
    • Tumor stroma niche (Bone marrow messenchymal stem cells)
    • Tumor associated macrophages (TAMs)
    • Reprogramming Cancer stem cells
    • Impact of Microbial Sensing in Cancer progression
    • Pre-cancer program (Barrett's, colorectal polyp, gastric metaplasia)
  • Neuronal disorders
    • Alzheimer's
    • Autism

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

  • Standard protein chemistry
  • Standard molecular biology
  • Computational chemistry (collaborative)
  • Immunofluorescence
  • Electron microscopy and Immuno-EM
  • Immuno-histochemistry
  • Live-cell imaging
  • Systems Engineering
  • Computational and Bioinformatic analyses of 'big data' a variety of model systems...
  • Mammalian cell lines in 2D cultures, genetically edited with shRNA or CRISPR/Cas9
  • Rodents (mice)
  • Patient-derived organoids
  • Patient-derived primary cells (immune and non-immune)
  • Live microbes (Pathogens and non-Pathogens)