# Regulation of Intracellular Signaling

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $516,338

## Abstract

Summary (30 lines)
Our research program aims to understand how cells control intracellular signaling to respond and adapt to their
environments. We will focus on three processes: Project 1 will examine the chemotactic migration of cells in
extracellular chemical gradients, Project 2 will look at DNA repair after oxidative, genotoxic, and mechanical
stress, and Project 3 will investigate the reprogramming of cell proliferation signaling in response to receptor
tyrosine kinase inhibition.
Project 1: GTPases are crucial for signal transduction in many cellular activities. Recently, we discovered an
unforeseen, evolutionarily conserved mechanism by which GDP-bound Rho GTPase activates mTORC2, a
critical serine/threonine kinase, in Dictyostelium and human cells. We will investigate the fundamental
mechanism underlying this novel regulation of small GTPases using the robust chemotactic signaling in
Dictyostelium cells as a discovery tool supported by an array of cutting-edge technologies. Successful
outcomes will broadly impact tissue development, wound healing, neuronal wiring, and immune responses, as
chemotaxis is crucial for these essential processes.
Project 2: PTEN protects the genome from stress in the nucleus. PTEN accumulates in the nucleus upon
stress via ubiquitin signaling. Identifying the ubiquitin ligase that controls PTEN after stress represents a critical
knowledge gap in our understanding of PTEN's stress signaling. Using a genome-wide CRISPR screen, we
will comprehensively test the function of E3 ligases under various forms of stress, such as oxidative, genotoxic,
and mechanical stress. We will subsequently investigate how stress regulates the ubiquitin ligases.
Project 3: Cells can adapt to unfavorable surroundings and weakened physiology by rearranging signal
transduction pathways. We will analyze how cells alter signaling networks when the activity of vital signaling
components is inhibited using innovative approaches, including AI-based multiplexed biosensor barcoding. We
focus on the EGF receptor, which is essential for physiology and development. Outcomes will reveal the basic
mechanisms by which cells can rewire signal transduction pathways and bypass the inhibition of essential
signaling elements.

## Key facts

- **NIH application ID:** 10838113
- **Project number:** 2R35GM131768-06
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Miho Iijima
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $516,338
- **Award type:** 2
- **Project period:** 2019-06-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838113

## Citation

> US National Institutes of Health, RePORTER application 10838113, Regulation of Intracellular Signaling (2R35GM131768-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10838113. Licensed CC0.

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