Identification of Op18/stathmin as a potential target of ASK1‐p38 MAP kinase cascade

Abstract 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 (ASK1ΔN) in PC12 cells. The ASK1‐dependent increase in the phosphorylation of Op18/stathmin was attenuated by the treatment with SB203580, suggesting that p38α and/or p38β 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 p38α was the dominantly expressed isoform in PC12 cells, ASK1‐induced phosphorylation of Op18/stathmin appears to be mediated mainly through p38α 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. J. Cell. Physiol. 206: 363–370, 2006. © 2005 Wiley‐Liss, Inc.