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

The alkylating agent methylmethanesulfonate (MMS) activates the c-jun N-ter minal kinase (JNK)/stress-activated protein kinase (SAPK) and the p38 mitog en-activated protein kinase (p38MAPK) pathways via different mechanisms of action. Activation of p38MAPK by MMS involves the pp125 focal adhesion kina se-related tyrosine kinase RAFTK and the MARK kinase 3. The way in which MM S can activate JNK/SAPK has not been elucidated. Here we describe the ident ification 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 huma n diploid skin fibroblasts and in simian virus 40-transformed skin fibrobla sts, indicating that the enhanced expression of MIG-6 after MMS-treatment d id not require p53. The signal leading to activation of MIG-6 appeared to b e 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 inducti on of MIG-6. (C) 2001 Wiley-Liss, Inc.