Identification of Op18/stathmin as a potential target of ASK1-p38 MAP kinase cascade.
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein (MAP) kinase kinase kinase that activates the JNK and p38 MAP kinase cascades and has a broad range of biological activities including cell differentiation and stress-induced apoptosis. However, effector molecules of ASK1-MAP kinase cascades that exert such activities have not been fully identified. Here we have identified oncoprotein 18 (Op18)/stathmin as a potential target of the ASK1-p38 cascade. By two-dimensional electrophoresis, phosphorylation of Op18/stathmin was found to be increased upon the expression of constitutively active ASK1 (ASK1DeltaN) in PC12 cells. The ASK1-dependent increase in the phosphorylation of Op18/stathmin was attenuated by the treatment with SB203580, suggesting that p38alpha and/or p38beta contribute to the phosphorylation of Op18/stathmin. Consistently, we found that all four isoforms of p38 directly phosphorylated Op18/stathmin primarily at serine 25 in vitro. Taken together with the quantitative RT-PCR data indicating that p38alpha was the dominantly expressed isoform in PC12 cells, ASK1-induced phosphorylation of Op18/stathmin appears to be mediated mainly through p38alpha in these cells. Given that the microtubule-destabilizing activity of Op18/stathmin is regulated by its phosphorylation, the ASK1-p38 cascade may regulate microtubule dynamics through Op18/stathmin.
Mizumura
Kenji
K
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, and CREST, Japan Science and Technology Corporation, Tokyo, Japan.
Takeda
Kohsuke
K
Hashimoto
Shu
S
Horie
Takashi
T
Ichijo
Hidenori
H
D000595:Amino Acid Sequence; D000818:Animals; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D050777:Stathmin / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D050777:Stathmin; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C093642:SB 203580