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

Abstract

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.