MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation.

Academic Article

Abstract

  • The cellular response to DNA damage is mediated by evolutionarily conserved Ser/Thr kinases, phosphorylation of Cdc25 protein phosphatases, binding to 14-3-3 proteins, and exit from the cell cycle. To investigate DNA damage responses mediated by the p38/stress-activated protein kinase (SAPK) axis of signaling, the optimal phosphorylation motifs of mammalian p38alpha SAPK and MAPKAP kinase-2 were determined. The optimal substrate motif for MAPKAP kinase-2, but not for p38 SAPK, closely matches the 14-3-3 binding site on Cdc25B/C. We show that MAPKAP kinase-2 is directly responsible for Cdc25B/C phosphorylation and 14-3-3 binding in vitro and in response to UV-induced DNA damage within mammalian cells. Downregulation of MAPKAP kinase-2 eliminates DNA damage-induced G2/M, G1, and intra S phase checkpoints. We propose that MAPKAP kinase-2 is a new member of the DNA damage checkpoint kinase family that functions in parallel with Chk1 and Chk2 to integrate DNA damage signaling responses and cell cycle arrest in mammalian cells.
  • Authors

  • Manke, Isaac A
  • Nguyen, Anhco
  • Lim, Daniel
  • Stewart, Mary
  • Elia, Andrew EH
  • Yaffe, Michael B
  • Status

    Publication Date

  • January 7, 2005
  • Published In

  • Molecular Cell  Journal
  • Keywords

  • 14-3-3 Proteins
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Apoptosis
  • Base Sequence
  • Catalytic Domain
  • Cell Cycle
  • Cell Cycle Proteins
  • Cell Line
  • DNA Damage
  • Humans
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Models, Biological
  • Models, Molecular
  • Phosphorylation
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Static Electricity
  • Ultraviolet Rays
  • cdc25 Phosphatases
  • p38 Mitogen-Activated Protein Kinases
  • Digital Object Identifier (doi)

    Pubmed Id

  • 15629715
  • Start Page

  • 37
  • End Page

  • 48
  • Volume

  • 17
  • Issue

  • 1