# Elucidating structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling.

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $172,575

## Abstract

Taylor, Martin | K08 (PA-20-203) | PROJECT SUMMARY / ABSTRACT
This proposal details a five-year training plan for the development of a research program focused on elucidating
structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling. Phosphorylation
of the signaling kinase Akt on Ser473 by mTOR Complex 2 (mTORC2) is a critical regulated intracellular step in
insulin and other growth factor signaling. Ser473 phosphorylation activates Akt and is required for Akt’s
downstream metabolic effects, such as glucose transporter upregulation, which are dysregulated in diabetes,
and proliferation and growth, which are dysregulated in cancer. Therapeutic modulation of mTORC2 is therefore
of interest in the treatment of both diabetes and cancer but is not yet possible due to similarities between
mTORC2 and the better-understood effector complex mTORC1, which shares key components mTOR and
mLST8. mTORC2 also activates other substrates with less-defined roles in ion channel homeostasis, apoptosis,
cell motility, metastasis, and insulin receptor sensitivity, and its activity is modulated by a series of allosteric
interacting proteins including the small GTPases Rho and Ras. However, despite the central role of mTORC2-
Akt signaling, we have little information about how this critical reaction is catalyzed by mTORC2, how mTORC2
recognizes Akt and other substrates, or how these interactions are modulated allosterically. This project therefore
seeks to develop a detailed structural and mechanistic understanding of mTORC2 recognition of its substrates,
using novel enzymologic assays, protein engineering, and a combination of biochemical, chemical, proteomic,
and structural biology approaches that will also develop proof-of-concept inhibitors and potentially activators of
mTORC2.
My proposed studies will:
(i) provide detailed structural and mechanistic insight into mTOR Complex 2 kinase signaling
(ii) develop tools, reagents, and techniques applicable to other systems of interest, including mTORC1
(iii) provide ample opportunities for mechanistic and translational follow-up for my transition to independence.
I am a practicing gastrointestinal pathologist and physician scientist seeking K08 support for mentored research
under the guidance of Dr. David Sabatini and Dr. Philip Cole. This mentored period of 80% research and career
development and 20% clinical time will ensure I acquire the skills required to become a successful independent
principal investigator. Drs. Sabatini and Cole are internationally recognized mentors, together training ~40
successful independent investigators. My training will occur at two world-class institutions, the Whitehead
Institute for Biomedical Research, and Massachusetts General Hospital Department of Pathology. Both are rich
with opportunities for young scientists to train, pursue highly impactful science, and foster long-lasting
collaborations. I will also be guided by a committee of researchers that are ...

## Key facts

- **NIH application ID:** 10284076
- **Project number:** 1K08DK129824-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MARTIN S TAYLOR
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $172,575
- **Award type:** 1
- **Project period:** 2021-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284076

## Citation

> US National Institutes of Health, RePORTER application 10284076, Elucidating structural, mechanistic, and allosteric determinants of mTOR Complex 2 (mTORC2) signaling. (1K08DK129824-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10284076. Licensed CC0.

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