Abstract
Polo-like kinase 1 (Plk1) is an instrumental kinase that modulates many aspects of the cell cycle. Previous investigations have indicated that Plk1 is a target of the DNA damage response, and Plk1 inhibition is dependent on ATM/ATR and Chk1. But the exact mechanism remains elusive. In a proteomic screen to identify Chk1-interacting proteins, we found that myosin phosphatase targeting protein 1 (MYPT1) was present in the immunocomplex. MYPT1 is phosphorylated by CDK1, thus recruiting protein phosphatase 1β (PP1cβ) to dephosphorylate and inactivate Plk1. Here we identified that Chk1 directly interacts with MYPT1 and preferentially phosphorylates MYPT1 at Ser20, which is essential for MYPT1-PP1cβ interaction and subsequent Plk1 dephosphorylation. Phosphorylation of Ser20 is abolished during mitotic damage when Chk1 is inhibited. The degradation of MYPT1 is also regulated by Chk1 phosphorylation. Our results thus unveil the underlying machinery that attenuates Plk1 activity during mitotic damage through Chk1-induced phosphorylation of MYPT1.
Keywords:
Cell cycle; DNA damage; MYPT1; PP1cβ; Plk1; mitosis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Animals
-
Ataxia Telangiectasia Mutated Proteins / metabolism
-
CDC2 Protein Kinase / chemistry
-
CDC2 Protein Kinase / metabolism*
-
Cell Cycle Proteins / metabolism
-
HEK293 Cells
-
HeLa Cells
-
Humans
-
Mitosis
-
Myosin-Light-Chain Phosphatase / chemistry
-
Myosin-Light-Chain Phosphatase / metabolism*
-
Phosphopeptides / analysis
-
Phosphorylation
-
Polo-Like Kinase 1
-
Protein Binding
-
Protein Phosphatase 1 / chemistry
-
Protein Phosphatase 1 / metabolism*
-
Protein Serine-Threonine Kinases / metabolism
-
Proteomics
-
Proto-Oncogene Proteins / metabolism
-
Serine / metabolism
Substances
-
Cell Cycle Proteins
-
Phosphopeptides
-
Proto-Oncogene Proteins
-
Serine
-
Ataxia Telangiectasia Mutated Proteins
-
Protein Serine-Threonine Kinases
-
CDC2 Protein Kinase
-
Protein Phosphatase 1
-
Myosin-Light-Chain Phosphatase
-
PPP1R12A protein, human
Grants and funding
National Natural Science Foundation of China [grant number 31530016]; National Natural Science Foundation of China [grant number 31761133012]; Shenzhen Science and Technology Innovation Commission [grant number JCYJ20170412112009742]; the National Key R&D Program of China projects [grant number 2015CB910601], [grant number 2017YFA0503900]; Beijing Nova Program Interdisciplinary Cooperation Project [grant number Z161100004916042]; CNU Interdisciplinary Project.