PRO-INFLAMMATORY CYTOKINES AND ENVIRONMENTAL-STRESS CAUSE P38 MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION BY DUAL PHOSPHORYLATION ON TYROSINE AND THREONINE

Protein kinases activated by dual phosphorylation on Tyr and Thr (MAP kinases) can be grouped into two major classes: ERK and JNK. The ERR g roup regulates multiple targets in response to growth factors via a Ra s-dependent mechanism, In contrast, JNK activates the transcription fa ctor c-Jun in response to pro-inflammatory cytokines and exposure of c ells to several forms of environmental stress, Recently, a novel mamma lian protein kinase (p38) that shares sequence similarity with mitogen -activated protein (MAP) kinases was identified, Here, we demonstrate that p38, like JNK, is activated by treatment of cells with pro-inflam matory cytokines and environmental stress, The mechanism of p38 activa tion is mediated by dual phosphorylation on Thr-180 and Tyr-182, Immun ofluorescence microscopy demonstrated that p38 MAP kinase is present i n both the nucleus and cytoplasm of activated cells, Together, these d ata establish that p38 is a member of the mammalian MAP kinase group.