title: Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis.
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.
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Departments of Physiology and Biophysics and of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Biological Sciences, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Sourav
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Departments of Physiology and Biophysics and of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, University of California-San Diego, La Jolla, California 92093, USA.|Departments of Cellular and Molecular Medicine and of Chemistry and Biochemistry, University of California-San Diego, La Jolla, California 92093, USA.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Dixon
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D064113:CRISPR-Cas Systems; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008819:Mice, Nude; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013912:Threonine; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000097603:Dyrk Kinases
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D013912:Threonine; D000097603:Dyrk Kinases; C088863:PSMC4 protein, human