The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP kinases.
We previously reported that nuclear translocation is essential for p42/p44 MAPKs (ERKs) mitogenic signaling. Here we show that, during long-term stimulation, p42/p44 MAPKs become inactive while they accumulate in the nucleus. This inactivation was monitored by phospho-specific immunostaining and dephosphorylation of a nuclear p42/p44 MAPKs substrate, HIF-1 alpha. The phosphatases responsible for p42/p44 MAPKs nuclear inactivation are neo-synthesized, show tyrosine or dual specificity, and interact with p42/p44 MAPKs via a specific docking site. Likely candidates are MKP1/2 phosphatases. In addition, p42/p44 MAPKs permanently shuttle between the cytoplasm and the nucleus in quiescent as well as in serum stimulated cells. Hence, the nucleus is a critical site for mitogenic signal termination by: (1) nuclear sequestration of p42/p44 MAPKs away from MEK, their cytoplasmic activator; and (2) dephosphorylation by specific nuclear phosphatases.
Volmat
V
V
Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR-6543, Centre Antoine Lacassagne, 06189 Nice, France. volmat@unice.fr
Camps
M
M
Arkinstall
S
S
Pouysségur
J
J
Lenormand
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002467:Cell Nucleus / Q000201:enzymology*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000201:enzymology; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008168:Lung / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D001798:Blood Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008934:Mitogens; D014157:Transcription Factors; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases