Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis

Xing Guo (Lead / Corresponding author), Xiaorong Wang, Zhiping Wang, Sourav Banerjee, Jing Yang, Lan Huang, Jack E. Dixon (Lead / Corresponding author)

Research output: Contribution to journalArticle

68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)202-212
Number of pages11
JournalNature Cell Biology
Volume18
Issue number2
Early online date14 Dec 2015
DOIs
Publication statusPublished - Feb 2016

Fingerprint Dive into the research topics of 'Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis'. Together they form a unique fingerprint.

  • Cite this