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The Regulation and Function of the Ubiquitin-Sensing Kinase TNK1

Award Number: R01GM147310
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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The Regulation and Function of the Ubiquitin-Sensing Kinase TNK1 - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	003	4	5/13/2025	NON-COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	002	3	12/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$237,719
2025	2023	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	001	2	12/9/2024	NON-COMPETING CONTINUATION	-$1
2025	2022	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	1	12/9/2024	NEW	-$237,718
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $336,670 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	002	4	6/13/2024	NON-COMPETING CONTINUATION	$323,400
2024	2023	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	2	10/27/2023	NON-COMPETING CONTINUATION	-$310,128
2024	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	001	3	10/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$323,398
														Subtotal = $336,670

Issue Date FY: 2023 ( Subtotal = $310,129 )
2023	2023	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	2	6/1/2023	NON-COMPETING CONTINUATION	$310,129
														Subtotal = $310,129

Issue Date FY: 2022 ( Subtotal = $310,363 )
2022	2022	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	1	8/17/2022	NEW	$310,363
														Subtotal = $310,363

Grand Total All Awards = $957,162

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The Regulation and Function of the Ubiquitin-Sensing Kinase TNK1

Award Number: R01GM147310

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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