# Regulation and function of TBK1-mTOR crosstalk

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $408,408

## Abstract

Project Summary
 Cellular and organismal homeostasis requires integration of diverse local and systemic cues by cell
signaling networks. The anabolic kinase mTOR (mechanistic target of rapamycin) integrates nutrient and
growth factor availability, playing critical roles in cellular processes that modulate metabolism, tumorigenesis,
and immune function. mTOR comprises the catalytic core of two functionally distinct, multi-subunit complexes,
mTORC1 and mTORC2. Not surprisingly, aberrant mTOR function contributes to pathological states including
obesity-linked type II diabetes, cancer, and immune disorders. Despite the physiological importance of mTOR,
major gaps exist in our mechanistic understanding of mTOR regulation and function, particularly how mTOR
communicates with other important regulatory systems to control cell and organismal physiology. Recent work
from our lab provides the scientific premise for this proposal, which demonstrated that the non-canonical
innate immune kinase TBK1 (TANK binding kinase 1) phosphorylates mTOR (on S2159) to increase mTORC1
and mTORC2 signaling upon cellular stimulation with innate immune agonists (e.g., the viral dsRNA mimetic
poly(I:C); bacterial LPS), growth factors (EGF), or hormones (insulin) in cultured cells and in vivo (Bodur et al.
2018; Tooley et al. 2021). This work linked two physiologically important signaling systems not previously
known to communicate. Classically, TBK1 responds to microbial-derived signals to initiate first-line host
defense against viral and bacterial pathogens. These signals lead to phosphorylation and activation of TBK1,
which drives ]production of type I interferons (e.g., IFNb) and IFN-stimulated genes (ISGs). More recent work
implicates TBK1 in a broader range of functions including improved glycemic control during diet-induced
obesity and tumorigenesis through poorly defined downstream mediators. We demonstrated recently that mice
bearing a “TBK1 resistant”, phosphorylation deficient Mtor S2159A allele display systemic insulin resistance
and hyperglycemia in the diet-induced obese but not the lean state (Bodur et al. 2022). Macrophages and
adipose tissue from these mice display reduced expression of IFNb and the anti-inflammatory ISG IL-10 as
well as elevated expression of pro-inflammatory cytokines (Bodur et al. 2022). The overarching goal of this
application is to elucidate the regulation and function of TBK1-mTOR crosstalk in cells and in vivo. We will
employ biochemical, cellular, and molecular approaches to better define how TBK1 promotes mTORC1 and
mTORC2 signaling in the absence of microbial-derived signals (Aim 1). We will also investigate how TBK1-
mTOR signaling protects against insulin resistance, hyperglycemia, and inflammation in the diet-induced obese
but not lean state by studying mice in vivo and primary cells in culture (Aim 2). This project will not only
elucidate basic mechanisms underlying control of TBK1-mTOR signaling but will also advance our knowl...

## Key facts

- **NIH application ID:** 10890758
- **Project number:** 5R01GM150679-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Diane C. Fingar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $408,408
- **Award type:** 5
- **Project period:** 2023-07-19 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890758

## Citation

> US National Institutes of Health, RePORTER application 10890758, Regulation and function of TBK1-mTOR crosstalk (5R01GM150679-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10890758. Licensed CC0.

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