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Chemoproteomic Profiling Uncovers CDK4-Mediated Phosphorylation of the Translational Suppressor 4E-BP1

54 Pages Posted: 7 Jan 2019 Sneak Peek Status: Published

See all articles by Dylan Mitchell

Dylan Mitchell

University of Michigan at Ann Arbor - Program in Chemical Biology

Arya Menon

University of Michigan at Ann Arbor, College of Pharmacy, Department of Medicinal Chemistry

Amanda L. Garner

University of Michigan at Ann Arbor - Program in Chemical Biology; University of Michigan at Ann Arbor, College of Pharmacy, Department of Medicinal Chemistry

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Abstract

Recent estimates of the human proteome suggest that there are ~20,000 protein-coding genes, the protein products of which contain >145,000 phosphorylation sites. Unfortunately, in-depth examination of the human phosphoproteome has far outpaced the ability to annotate the kinases that mediate these post-translational modifications. To obtain actionable information about phosphorylation-driven signaling cascades, it is essential to identify the kinases responsible for phosphorylating sites that differ across disease states. To fill in these knowledge gaps, we have developed an unbiased, chemoproteomic approach for identifying high confidence kinase-substrate interactions with phosphosite specificity. Using this assay, we have uncovered the role of cyclin-dependent kinase 4 (CDK4), a clinically validated kinase important for cell cycle progression, in regulating cap-dependent translation via phosphorylation of the tumor suppressor 4E-BP1. The discovery of this novel signaling axis sheds new light on the mechanisms by which CDK4/6 inhibitors control cell proliferation and constitutes the first example of successful kinase discovery using an activity-based, kinase-directed probe.

Suggested Citation

Mitchell, Dylan and Menon, Arya and Garner, Amanda L., Chemoproteomic Profiling Uncovers CDK4-Mediated Phosphorylation of the Translational Suppressor 4E-BP1 (November 20, 2018). Available at SSRN: https://ssrn.com/abstract=3287781 or http://dx.doi.org/10.2139/ssrn.3287781
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Dylan Mitchell

University of Michigan at Ann Arbor - Program in Chemical Biology

500 S. State Street
Ann Arbor, MI 48109
United States

Arya Menon

University of Michigan at Ann Arbor, College of Pharmacy, Department of Medicinal Chemistry

500 S. State Street
Ann Arbor, MI 48109
United States

Amanda L. Garner (Contact Author)

University of Michigan at Ann Arbor - Program in Chemical Biology ( email )

500 S. State Street
Ann Arbor, MI 48109
United States

University of Michigan at Ann Arbor, College of Pharmacy, Department of Medicinal Chemistry ( email )

500 S. State Street
Ann Arbor, MI 48109
United States

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