title: New Cdc2 Tyr 4 phosphorylation by dsRNA-activated protein kinase triggers Cdc2 polyubiquitination and G2 arrest under genotoxic stresses.
abstract: Cell division cycle 2 (Cdc2) protein is an essential subunit of M-phase kinase (MPK), which has a key role in G2/M transition. Even though the control of MPK activity has been well established with regard to the phosphorylation of Cdc2 at Thr 14 and/or Tyr 15 and Thr 161, little is known about the proteolytic control of Cdc2. In this study, we observed that Cdc2 was downregulated under genotoxic stresses and that double-stranded RNA-activated protein kinase (PKR) was involved in the process. The PKR-mediated Tyr4 phosphorylation triggered Cdc2 ubiquitination. Phospho-mimic mutations at the Tyr 4 residue (Y4D or Y4E) caused significant ubiquitination of Cdc2 even in the absence of PKR. Our findings demonstrate that (i) PKR, Ser/Thr kinase, phosphorylates its new substrate Cdc2 at the Tyr 4 residue, (ii) PKR-mediated Tyr 4-phosphorylation facilitates Cdc2 ubiquitination and proteosomal degradation, (iii) unphosphorylated Tyr 4 prevents Cdc2 ubiquitination, and (iv) downstream from p53, PKR has a crucial role in G2 arrest and triggers Cdc2 downregulation under genotoxic conditions.
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi-Do, South Korea.
authors.forename: Cheol-Hee
authors.initials: CH
authors.lastname: Yoon
authors.forename: Mohammad Alam
authors.initials: MA
authors.lastname: Miah
authors.forename: Kwang Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Bae
mesh_terms: D016203:CDC2 Protein Kinase / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D015536:Down-Regulation; D016195:G2 Phase; D045325:HCT116 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D054875:Ubiquitination; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D025821:Polyubiquitin; D019000:Phosphotyrosine; D019892:eIF-2 Kinase; D016203:CDC2 Protein Kinase
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