Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72

Various stresses activate the c-Jun N-terminal kinase (JNK), which is invol ved in the regulation of many aspects of cellular physiology, including apo ptosis, Here we demonstrate that in contrast to UV irradiation, heat shock causes little or no stimulation of the JNK-activating kinase SEK1, while kn ocking out the SEK1 gene completely blocks heat-induced JNK activation. The refore, we tested whether heat shock activates JNK via inhibition of JNK de phosphorylation, The rate of JNK dephosphorylation in unstimulated cells wa s high, and exposure to UV irradiation, osmotic shock, interleukin-1, or an isomycin did not affect this process. Conversely, exposure of cells to heat shock and other protein-damaging conditions, including ethanol, arsenite, and oxidative stress, strongly reduced the rate of JNK dephosphorylation. U nder these conditions, we did not observe any effects on dephosphorylation of the homologous p38 kinase, suggesting that suppression of dephosphorylat ion is specific to JNK, Together, these data indicate that activation of JN K by protein-damaging treatments is mediated primarily by inhibition of a J NK phosphatase(s), Elevation of cellular levels of the major heat shock pro tein Hsp72 inhibited a repression of JNK dephosphorylation by these stressf ul treatments, which explains recent reports of the suppression of JNK acti vation by Hsp72.