# Mechanisms Of Akt Regulation

> **NIH NIH K22** · OHIO STATE UNIVERSITY · 2021 · $187,272

## Abstract

Abstract:
The Ser/Thr protein kinase Akt1 is key signaling enzyme that participates in the regulation of cell growth and
other physiologic processes, and its dysregulation contributes to many cancers. Akt1 is a critical effector of the
cancer promoting phospholipid PIP3 (phosphatidyl inositol 3,4,5-triphosphate) signaling and is subject to
regulation by C-tail phosphorylation. Notably, mTORC2-mediated Akt C-tail phosphorylation on Ser473 acts as
a major, well-defined regulatory site and is commonly measured as a proliferative mark in cancer. Yet how
phosphorylation of Ser473, and auxiliary sites Ser477 and Thr479 modulate Akt1 structure and function has
been poorly defined. By employing protein semisynthesis approaches, our preliminary work has revealed that
Akt1 C-tail phosphorylation events at Ser473 and Ser477/Thr479 can relieve Akt1 autoinhibition using distinct
mechanisms. Our model for phospho-Ser473 activation proposes that phosphorylation of the C-terminus of
Akt1 can dislodge the Pleckstrin homology (PH) domain from the kinase domain and involves a phosphate
interaction with the PH-kinase linker. However, the conformational dynamics of the PH domain, linker tension,
and the structural basis of phospho-Ser477/phospho-Thr479-mediated activation represent key gaps in
understanding of Akt1 regulation. In addition, it has been unknown how mTORC2 complex recognizes and
phosphorylates the C-tail of Akt1 leading to its activation. The goals of this proposal are three-fold. 1) Delineate
the dynamic regulation of Akt1 through the C-tail phosphorylation by analyzing how the PH-kinase linker
flexibility influences pSer473’s impact on Akt activation and employing 15N/13C/2H NMR spectroscopy with
semisynthetic segmentally isotopically labeled Akt1 containing distinct phospho forms to characterize
conformational dynamics of Akt1. 2) Identify novel protein substrates phosphorylated by pSer477/pThr479 Akt1
by using protein microarrays along with other biochemical and cell-based methods. 3) Investigate the structural
and mechanistic basis of Akt1 activation by mTORC2 complex. These studies will provide new fundamental
insights into how the mTORC2-Akt cell signaling axis is regulated and can provide a framework for new
therapeutic strategies to combat dysregulation of these protein kinases in cancer. Furthermore, this career
development grant will augment my ability to succeed as an independent investigator by broadening my
experimental repertoire and supporting additional career enrichment. That is, K22 support will enhance my
immersion in pharmacology, structural biology, mass spectrometry, and cell-based studies in a premier
research environment and help me launch a successful independent academic career.

## Key facts

- **NIH application ID:** 9976789
- **Project number:** 1K22CA241105-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Nam Ky Chu
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $187,272
- **Award type:** 1
- **Project period:** 2021-04-19 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976789

## Citation

> US National Institutes of Health, RePORTER application 9976789, Mechanisms Of Akt Regulation (1K22CA241105-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976789. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*