# The regulation and function of the ubiquitin-sensing kinase TNK1

> **NIH NIH R01** · BRIGHAM YOUNG UNIVERSITY · 2022 · $310,363

## Abstract

PROJECT SUMMARY/ABSTRACT
Alterations in kinase signaling underlie many of the most devastating human diseases, including
degenerative disease, autoimmunity and cancer. Thus, not surprisingly, kinases are the second most
targeted group of drug targets (next to G-protein coupled receptors). Yet despite their importance in
disease, only about 8% of kinases are targets of FDA approved drugs and roughly a quarter of the
634 kinases in the human kinome is still considered ‘understudied’, leaving over 100 kinases
untapped as potential therapeutic targets and without clear biological functions. This proposal focuses
on TNK1, a poorly understood member of the ACK kinase family of non-receptor tyrosine kinases
(NRTKs). Our recently published data (Nat. Comm. 2021) uncovered the first mechanism of regulation
and the unusual presence of a ubiquitin-association (UBA) domain on this kinase. Critical gaps
relating to this mechanism and the still unknown cellular function of TNK1 are addressed in this
proposal. Our long-term goal is to discover mechanisms of cell growth and survival that can be
therapeutically targeted in disease. The overall objectives of this proposal are to establish the first
detailed mechanism and function of this understudied kinase. The central hypothesis is that the
binding of the TNK1 UBA domain to clusters of poly-ubiquitin at protein aggregate condensates acts
as a form of induced proximity to oligomerize and activate TNK1 (aim 1). We also hypothesize that the
interaction of 14-3-3 with phospho-Ser502 of TNK1 inhibits TNK1 oligomerization and conceals the
UBA domain, thereby sequestering TNK1 away from ubiquitin in an inactive state (aim 2). Finally, we
posit that TNK1 senses the accumulation of poly-ubiquitin to phosphorylate substrates that promote
the lysosomal degradation of condensates (aim 3). The proposal is significant because it fills a basic
gap in our understanding of TNK1, provides a framework to understand how mutations activate TNK1
in disease, and perhaps most importantly will inform pharmacological strategies that take advantage
of our recently developed TNK1 inhibitor to target TNK1 in disease. The proposal is innovative
because it addresses a novel mechanism of kinase activation through direct interaction with poly-
ubiquitin, thereby establishing condensates as organizing platforms for kinase signaling. In addition,
this proposal lays the first foundation to target TNK1 in disease.

## Key facts

- **NIH application ID:** 10502909
- **Project number:** 1R01GM147310-01
- **Recipient organization:** BRIGHAM YOUNG UNIVERSITY
- **Principal Investigator:** Joshua Lyon Andersen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $310,363
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10502909

## Citation

> US National Institutes of Health, RePORTER application 10502909, The regulation and function of the ubiquitin-sensing kinase TNK1 (1R01GM147310-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10502909. Licensed CC0.

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