# New Molecular Probes For Protein Kinases

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $328,436

## Abstract

The long-term objective of this project is to merge molecular tool development with functional
studies of kinases that are of biological interest. To date, we’ve developed new chemical tools for
modulating kinase regulatory interactions, global conformational state, and interactomes, which
we’ve used to understand how differentially modulating these parameters affects the intracellular
functions of protein kinases. During the previous funding period, we demonstrated that new and
unexpected mechanistic discoveries can be made on even the most well characterized kinases
through the application of new molecular analysis tools. We found that the phosphotransferase
activity of the tyrosine kinase Src is regulated by its N-terminal SH4 domain, which was previously
believed to only serve as a membrane tether. In this proposal, we will leverage many of the same
methodologies what we used to stusy Src in order obtain a detailed molecular understanding of
Lck, which is a Src-Family Kinase (SFK) that plays a specialized role in T cell receptor (TCR)
signaling. SFKs that contain identical domain architectures as Lck cannot replicate Lck’s role in
TCR signaling and our preliminary results suggest that Lck’s regulatory module is unique. Our
goal is to comprehensively profile the regulatory properties of Lck and to determine what makes
it unique amongst the SFKs. In three Aims, spanning enzymology, biochemistry, cell biology, and
chemoproteomics, we propose to study the intrinsic and extrinsic regulation of Lck and the
functional consequences of manipulating its regulatory apparatus during TCR signaling. In
addition, we describe a new technology for profiling the regulatory and conformational states of
kinases during TCR signaling.

## Key facts

- **NIH application ID:** 10539866
- **Project number:** 2R01GM086858-14
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Dustin J Maly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,436
- **Award type:** 2
- **Project period:** 2008-09-30 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10539866

## Citation

> US National Institutes of Health, RePORTER application 10539866, New Molecular Probes For Protein Kinases (2R01GM086858-14). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10539866. Licensed CC0.

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