MITOGEN-ACTIVATED PROTEIN-KINASE PHOSPHATASES INACTIVATE STRESS-ACTIVATED PROTEIN-KINASE PATHWAYS IN-VIVO

The c-Jun N-terminal protein kinases (JNKs), also called stress-activa ted protein kinases, are members of the growing family of serine/threo nine kinases in the mitogen-activated protein (MAP) kinase superfamily . Like other MAP kinases, JNKs are activated via phosphorylation on ad jacent threonine and tyrosine residues and can be inactivated by a uni que family of dual specificity phosphatases, called MAP kinase phospha tases (MKPs). MKPs are encoded by immediate early genes and induced in response to environmental stressors and growth factor stimulation. Tw o prevalent isoforms of MKP, MKP1 and MKP2, are co-expressed in a wide variety of cell types. In this study, we examined the actions of MKP1 and MKP2 on JNK1 and JNK2. JNK1 phosphorylation and activation was in hibited by expression of both MKP1 and MKP2, although MKP1 selectivity toward JNK1 appeared significantly higher than that of MKP2. In contr ast, JNK2 activity was inhibited by either phosphatase to similar degr ees. Both MKP1 and MKP2 were highly effective at blocking the activati on of the physiological target of JNK activation, the transcription fa ctor c-Jun. In PC12 cells, MKP1 and MKP2 are transcriptionally induced following stimulation by nerve growth factor. In these cells, UV ligh t-evoked JNK activation was reduced by pretreatment with nerve growth factor. Therefore, JNKs may be selective targets of MKP action in cert ain cells.