Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate.

The alkylating agent methylmethanesulfonate (MMS) activates the c-jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 mitogen-activated protein kinase (p38MAPK) pathways via different mechanisms of action. Activation of p38MAPK by MMS involves the pp125 focal adhesion kinase-related tyrosine kinase RAFTK and the MAPK kinase 3. The way in which MMS can activate JNK/SAPK has not been elucidated. Here we describe the identification by differential display of human mitogen-activated gene-6 (MIG-6) as a novel MMS-inducible gene. Induction of MIG-6 by MMS was found in human diploid skin fibroblasts and in simian virus 40-transformed skin fibroblasts, indicating that the enhanced expression of MIG-6 after MMS-treatment did not require p53. The signal leading to activation of MIG-6 appeared to be independent of DNA damage. High MIG-6 expression was found in the liver, lung, and placenta. MIG-6 is an adapter protein that binds to the activated form of cdc42Hs and to 14-3-3 proteins, thereby activating JNK/SAPKs. Our results suggest that activation of JNK/SAPKs by MMS may involve the induction of MIG-6. Copyright 2001 Wiley-Liss, Inc.