NIH grant: Cellular Regulation of Mutationally Activated G Proteins (1R35GM161509-01)

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NIH grant 1R35GM161509-01: Cellular Regulation of Mutationally Activated G Proteins
Institute: {'code': 'GM', 'abbreviation': 'NIGMS', 'name': 'National Institute of General Medical Sciences', 'admin_org_id': '12500024', 'admin_funding_url': ''}. PI: PHILIP B WEDEGAERTNER. Award: $431750.
Start: 2026-07-01T00:00:00.
Summary Heterotrimeric G proteins (αβγ) canonically link G protein-coupled receptors (GPCRs), activated by
a wide variety of extracellular signals, to a variety of intracellular responses. Although in the classical model,
GPCR activation of G proteins and subsequent G protein-mediated signaling occurs at the cell’s plasma
membrane, it is becoming increasingly clear that GPCR-mediated G protein signaling also happens, with
important physiological implications, at the cytoplasmic surface of intracellular organelles, such as
endosomes and Golgi. However, much less understood is how G protein α (Gα) subunits function
independently of GPCRs when they contain mutations that render them constitutively active. Understanding
signaling and regulation of mutationally activated Gα in cells is critical to enhance our knowledge of G protein
function in cells and also because somatic mutations have been found in many Gα in human disease
contexts, most prominently in cancer. All Gα appear to use almost identical molecular mechanisms for binding
GDP or GTP and for hydrolyzing GTP back to GDP; mutations at one of two hotspot residues, a catalytic
glutamine (Q) or arginine (R), cause inhibition of the GTP hydrolysis turn-off mechanism resulting in a
constitutively active Gα and dysregulated signaling. In one of the most dramatic examples of mutational
activation of Gα, the highly similar Gαq and Gα11 subunits have been identified in over 90% of patients with
uveal melanoma where the constitutively active Gαq and Gα11 serve as oncogenic drivers. Despite the
pathophysiological importance of mutationally activated Gα, the cellular function and regulation of such
mutant Gα remain poorly understood. Generally, it has been assumed that mutationally activated Gα are
essentially GPCR-activated Gα and indeed mutant Gα are typically used as tools in model systems as
surrogates for GPCR-activated Gα. Recently, our work and the work of others is challenging this idea, by
uncovering unique properties and mechanisms of constitutively active Gα mutants. This research project will
take a broad approach and comprehensive analysis to identify new cellular mechanisms that regulate
mutationally activated Gα by investigating multiple Gα families, most prominently Gαq and Gαs subunits, and
multiple activating mutations, naturally occurring and not. We will investigate signaling by mutationally
activated Gα at intracellular locations, define how distinct mutations direct differences in signaling and
regulation, and gain further insight into unique mechanisms of regulation by addressing the paradoxical ability
of the natural product YM-254890 to inhibit mutationally activated forms of Gαq. Our work will address these
issues using a variety approaches, including biochemical approaches, signaling assays, fluorescence
microscopy, live cell imaging, and proteomic approaches to identify novel interactomes and signaling
pathways. Ultimately, a better understanding of the cellular mechanisms regulating signaling by mutationally
activated Gα may lead to ways to therapeutically target the mutant Gα while leaving the wild type Gα intact.

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