# Project 1

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $946,648

## Abstract

PROJECT SUMMARY/ABSTRACT
This application is a renewal of an ongoing project in which four investigators with different but complementary
expertise have worked together to understand how the T cell antigen receptor (TCR) regulates the proximal
tyrosine kinases (SFKs, Syk kinases and Tec kinases) that control critical downstream tyrosine
phosphorylation. We have made considerable progress in understanding the structural basis for the specificity
differences that are encoded in the kinase domains and the autoregulatory constraints that control the activities
of these kinases, but a full understanding will require new approaches. We propose to capitalize on our
current progress and bring together approaches from structural biology, physical sciences, proteomics,
immunology, and computational biology to perform studies that are aimed at understanding the distinct
features of the T cell-expressed SFKs, Syk and Tec kinases that make the individual kinases more suitable for
antigen receptor signaling in T cells than in B cells. We hypothesize that the characteristics of Lck and
Fyn, ZAP-70 and Itk and their signaling regulators have been optimized in T cells to establish signaling
circuitry that serves to maintain a basal signaling state that is resistant to perturbations by non-
agonist peptides and also establishes a sensitive threshold for optimal recognition and response to
agonist pMHC. We will explore this hypothesis in experiments designed to: 1) understand the unique features
of the proximal kinases that are advantageous in TCR signaling; 2) define the regulatory mechanisms that
constrain the activity of the proximal tyrosine kinases; 3) determine how TCRs maintain basal homeostasis and
distinguish biological noise from antigenic stimuli; and, 4) define the key intracellular events needed to initiate
downstream signal propagation by the TCR.

## Key facts

- **NIH application ID:** 9966855
- **Project number:** 5P01AI091580-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ARTHUR WEISS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $946,648
- **Award type:** 5
- **Project period:** 2011-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966855

## Citation

> US National Institutes of Health, RePORTER application 9966855, Project 1 (5P01AI091580-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9966855. Licensed CC0.

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