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Updated: Oct 20, 2025

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

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TNK1 is a ubiquitin-binding and 14-3-3-regulated kinase that can be targeted to block tumor growth

Tsz-Yin Chan1,2, Christina M Egbert1,2, Julia E Maxson3,4

  • 1Fritz B. Burns Cancer Research Laboratory, Brigham Young University, Provo, UT, USA.

Nature Communications
|September 10, 2021
PubMed

Insights

TNK1 (tyrosine kinase non-receptor 1) activity is regulated by MARK-mediated phosphorylation and ubiquitin binding. Disrupting these interactions inhibits TNK1, offering a potential cancer therapy target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • TNK1 (tyrosine kinase non-receptor 1) is a kinase with unclear biological roles.
  • Understanding TNK1 regulation is crucial for its potential therapeutic applications in cancer.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of TNK1.
  • To identify TNK1 dependencies in human cancers.
  • To discover novel therapeutic strategies targeting TNK1.

Main Methods:

  • Investigated TNK1 dependencies in primary human cancers.
  • Utilized MARK-mediated phosphorylation and ubiquitin-binding assays.
  • Employed cell culture and mouse models for in vivo studies.
  • Screened for TNK1 inhibitors.

Main Results:

  • Identified MARK-mediated phosphorylation at S502, promoting 14-3-3 binding and TNK1 inhibition.
  • Demonstrated that release from 14-3-3 allows TNK1 activation via ubiquitin binding.
  • Showed active TNK1 drives lymphoid cell proliferation independently of growth factors.
  • Characterized the TNK1 ubiquitin-association domain (UBA), essential for kinase activity.
  • Discovered TP-5801, a potent TNK1 inhibitor effective in vitro and in vivo.

Conclusions:

  • TNK1 activity is controlled by a switch between inactive 14-3-3-bound and active ubiquitin-bound states.
  • TNK1 UBA domain is critical for its function.
  • TP-5801 represents a promising therapeutic agent for TNK1-dependent cancers.

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