# Canonical and non-canonical RasGEF pathways in T cells

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $394,688

## Abstract

ABSTRACT – PROJECT 4
 T cells demonstrate remarkable sensitivity to activating TCR signals triggered by agonist pMHC
recognition. These signals elicit T cell activation as well as differentiation in effector T cell subsets to coordinate
immune protection to different pathogens, but the molecular basis for specific and dependable discrimination
and mechanistic regulation of T cell commitment (kinetic proofreading) are not understood. How the
discrimination between activating TCR signals triggered by agonist pMHC recognition versus self-pMHC
encounters occurs at a mechanistic level will be investigated in Projects 1-3, with focus on the proximal kinase
network, proofreading mechanisms through feedback loops, and LAT condensation characteristics. How the
TCR pathway converts incoming signals as a function of agonist pMHC recognition or self-pMHC encounters
and processes this information into instructive Effector Kinase Signals that control T cell activation and
differentiation will be investigated in Project 4.
 In Project 4, we will test our hypothesis that - downstream of the LAT signalosome - Effector Kinase
Signals triggered by two Ras Guanine nucleotide Exchange Factors (RasGEFs), SOS1 and RasGRP1 regulate
controlled and balanced T cell activation and differentiation. Specifically, we propose that agonist pMHC
recognition triggers the collective output of multiple RasGEF-Effector Kinase Signals that drive T cell activation
and proliferation in a failsafe and efficient manner. Unique nuances in the RasGEF-Effector Kinase effector
signals further influence development into effector T cell subsets, like regulatory T cells. By contrast, we propose
that contacts with self-pMHC do not trigger the same RasGEF signals, but instead, convert self-pMHC induced
sub-threshold, tonic signals into unique RasGEF signals that promote T cell survival and homeostasis. In Aim
1, we will Investigate RasGEF substrates and partner molecules in canonical and non-canonical pathways. In
Aim 2, we will assess tonic RasGRP1-mTOR signals and in vivo relevance in T cells. In Aim 3, we will establish
the functional significance of digital SOS1-Ras-ERK signaling in T cells and regulated immunity. In Aim 4, we
will decipher non-canonical SOS1-P38 signaling in regulatory T cells and tumor immunity.
 Our past and ongoing, collaborative efforts and seminal discoveries on two Ras Guanine nucleotide
Exchange Factors (RasGEFs), SOS and RasGRP, their canonical signals to Ras/MAPK pathways, their
unexpected non-canonical signals to mTOR and P38- kinase pathways, and innovative technologies form the
foundation for the four Aims of Project 4 in this revised P01 renewal. The Kuriyan-, Groves-, Salomon-, and
Roose- teams are poised to address the major questions in T cell biology described in Project 4. Together, these
studies will provide critical results how the TCR pathway converts incoming signals (Projects 1-3) into instructive
signals (Project 4) that control T cell activation and d...

## Key facts

- **NIH application ID:** 10428141
- **Project number:** 2P01AI091580-11A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JEROEN ROOSE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $394,688
- **Award type:** 2
- **Project period:** 2011-07-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428141

## Citation

> US National Institutes of Health, RePORTER application 10428141, Canonical and non-canonical RasGEF pathways in T cells (2P01AI091580-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428141. Licensed CC0.

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