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Nat Cell Biol. 2016 Feb;18(2):202-12. doi: 10.1038/ncb3289. Epub 2015 Dec 14.

Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis.

Author information

1
Department of Pharmacology, University of California-San Diego, La Jolla, California 92093, USA.
2
Departments of Physiology and Biophysics and of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
3
Division of Biological Sciences, University of California-San Diego, La Jolla, California 92093, USA.
4
Departments of Cellular and Molecular Medicine and of Chemistry and Biochemistry, University of California-San Diego, La Jolla, California 92093, USA.

Abstract

Despite the fundamental importance of proteasomal degradation in cells, little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological processes. Here we show that the proteasome is dynamically phosphorylated during the cell cycle at Thr 25 of the 19S subunit Rpt3. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrate that blocking Rpt3-Thr25 phosphorylation markedly impairs proteasome activity and impedes cell proliferation. Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. Importantly, loss of the single phosphorylation of Rpt3-Thr25 or knockout of DYRK2 significantly inhibits tumour formation by proteasome-addicted human breast cancer cells in mice. These findings define an important mechanism for proteasome regulation and demonstrate the biological significance of proteasome phosphorylation in regulating cell proliferation and tumorigenesis.

PMID:
26655835
PMCID:
PMC4844191
DOI:
10.1038/ncb3289
[Indexed for MEDLINE]
Free PMC Article

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