# Regulation of Heterotrimeric G proteins by non-receptor activators

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $343,200

## Abstract

Summary/Abstract:
Heterotrimeric G proteins are the major intracellular enzymes that receive signals from plasma membrane G
protein coupled receptors (GPCRs) and transduce them to a broad array of intracellular effectors. Our lab has
contributed much to the understanding of the function of a pair of G protein regulators, Ric-8A and Ric-8B. We
identified Ric-8A and Ric-8B as G protein  subunit binding proteins and showed that they possess the ability
to accelerate the rate at which G subunits release GDP and bind GTP. This activity is similar to GPCR action
towards G protein heterotrimers. GPCRs stimulate G protein GDP/GTP exchange for the purpose of activating
the G proteins to transmit signals. We have yet to find conclusive evidence that Ric-8 proteins facilitate G
GDP/GTP exchange for signaling purposes. We did find that deletion of the Ric-8A or Ric-8B genes in mice
caused embryonic lethality. Culture of Ric-8A or Ric-8B knockout embryonic stem cells that were attained from
viable embryos prior to death demonstrated that the cells had dramatically reduced levels of G proteins. This
prompted our investigation into the role that Ric-8 proteins have in regulating G protein abundance. We found
that Ric-8 proteins are molecular chaperones that facilitate protein folding of newly made G subunits. When
G proteins are made in cells lacking Ric-8 proteins, they are misfolded and rapidly degraded. We reconcile the
in vitro GDP/GTP exchange stimulatory activity of Ric-8 with the folding function by proposing that Ric-8
proteins bind the intermediate of the in vitro exchange reaction in cells, newly-synthesized, nucleotide-free G
proteins to facilitate first time GTP binding. Until now, all evidence indicated that Ric-8 proteins acted
constitutively to fold G proteins. The premise of this new application is based on our recent data that show that
Ric-8 activities are subject to dramatic regulation by post-translational phosphorylation. We will investigate a
new link between mitogenic oncogene stimulus that leads to Ric-8 deregulation (dephosphorylation) and
possible remodeling of cellular G protein levels. We have made important strides in our long-time collaborative
efforts to investigate the structural basis by which Ric-8 proteins regulate G proteins. The work in this
application will define the way that phosphorylation regulates Ric-8 function.

## Key facts

- **NIH application ID:** 9994927
- **Project number:** 5R01GM088242-12
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Gregory Gordon Tall
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,200
- **Award type:** 5
- **Project period:** 2009-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994927

## Citation

> US National Institutes of Health, RePORTER application 9994927, Regulation of Heterotrimeric G proteins by non-receptor activators (5R01GM088242-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9994927. Licensed CC0.

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