Mechanisms regulating the nuclear translocation of p38 MAP kinase

J Cell Biochem. 2010 Aug 15;110(6):1420-9. doi: 10.1002/jcb.22675.

Abstract

p38 mitogen-activated protein kinase (MAPK) is of fundamental importance in a cell's response to environmental stresses, cytokines and DNA damage. p38 resides in the cytoplasm of resting cells, and translocates into the nucleus upon activation, yet the exact mechanisms remain largely unclear. We show here that the phosphorylation-dependent nuclear translocation of p38 is a common phenomenon when cells are stimulated with various stresses. On the other hand, the nuclear export of p38 requires its dephosphorylation, and it is exported both in a MK2-dependent and a nuclear export signal (NES)-independent manner. Although different p38-regulated/activated protein kinase (PRAK) mutants all dictate the intracellular localization of p38, results from a PRAK-deficient cell line indicate that it plays no role in this process. Microtubule depolymerizing reagent nocodazole and dynein inhibitor EHNA both block the nuclear translocation of p38, demonstrating roles for microtubules and dynein in p38 transport. Taken together, stress-induced nuclear accumulation of p38 is a phosphorylation-dependent, microtubule- and dynein-associated process.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Arsenites / pharmacology
  • Blotting, Western
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Dyneins / antagonists & inhibitors
  • Dyneins / metabolism
  • Embryo, Mammalian / cytology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microtubules / metabolism
  • Mutation
  • NIH 3T3 Cells
  • Nocodazole / pharmacology
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Tubulin Modulators / pharmacology
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Arsenites
  • Intracellular Signaling Peptides and Proteins
  • Recombinant Fusion Proteins
  • Tubulin Modulators
  • Green Fluorescent Proteins
  • 9-(2-hydroxy-3-nonyl)adenine
  • MAP-kinase-activated kinase 5
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Dyneins
  • Adenine
  • arsenite
  • Nocodazole