# Conformational Control of Protein Kinases

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $300,300

## Abstract

Abstract. Protein kinases (PKs) play an essential role in cell signaling and in the regulation of key biological
processes, including: proliferation, differentiation, and apoptosis. Protein kinase mediated signaling is vital for
healthy (and disease) cell signaling, however, our efforts to understand these complex signaling pathways has
been hampered by an underappreciation and lack of tools to study the noncatalytic functions of protein
kinases. For many kinases, there is a stunning disconnect between cellular signaling when perturbed by
genomic knockdown (e.g., siRNA) vs pharmacological inhibition. We believe that this disconnect between
genomic and pharmacological intervention results from noncatalytic kinase functions being perturbed by
genomic knockdown, but not by traditional pharmacological intervention. One salient example is c-Src, a
ubiquitously expressed and membrane-associated nonreceptor kinase. c-Src has been validated as a key
target for many solid tumors via genomic knockdown, however, pharmacological inhibition (both in the clinic
and in pre-clinical models) leads to a divergent signaling phenotype and does not support c-Src as a
therapeutic target. Toward understanding the noncatalytic roles of c-Src, we recently reported that c-Src can
activate EGFR via a protein–protein interaction and that this activation has a dramatic impact on cell signaling.
Many PKs, including c-Src, are multi-domain proteins with regulatory domains that function in tandem with,
as well as independent to, the kinase catalytic domain. The noncatalytic functions of PKs are often dependent
on binding interactions between the regulatory domains and an interacting partner (e.g., c-Src and EGFR).
These protein–protein interactions are modulated by global conformational changes that alter the quaternary
structure of the kinase. Despite the emerging role of noncatalytic kinase signaling, efforts to understand the
importance of kinase conformation on signaling pathways have been hampered by a lack of tools to assess
and modulate the global conformation of PKs. As a result, we recently developed a ‘selective proteolysis’
technique to rapidly determine global kinase conformation that is adaptable to many PKs (including c-Src).
Additionally, we recently reported that an emerging class of kinase inhibitors, termed ‘conformation-selective’
kinase inhibitors, can modulate the noncatalytic functions of protein kinases via stabilization of specific kinase
conformations. Here, we propose to use our selective-proteolysis technique to develop genetic and chemical
tools to study the relationship of kinase conformation on noncatalytic kinase signaling.

## Key facts

- **NIH application ID:** 9964850
- **Project number:** 5R01GM125881-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MATTHEW B SOELLNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $300,300
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964850

## Citation

> US National Institutes of Health, RePORTER application 9964850, Conformational Control of Protein Kinases (5R01GM125881-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9964850. Licensed CC0.

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