SIGNAL-TRANSDUCTION BY TUMOR-NECROSIS-FACTOR MEDIATED BY JNK PROTEIN-KINASES

JNK protein kinases are distantly related to mitogen-activated protein kinases (ERKs) and are activated by dual phosphorylation on Tyr and T hr. The JNK protein kinase group includes the 46-kDa isoform JNK1. Her e we describe the molecular cloning of a second member of the JNK grou p, the 55-kDa protein kinase JNK2. The activities of both JNK isoforms are markedly increased by exposure of cells to UV radiation. Furtherm ore, JNK protein kinase activation is observed in cells treated with t umor necrosis factor. Although both JNK isoforms phosphorylate the NH2 -terminal activation domain of the transcription factor c-Jun, the act ivity of JNK2 was approximately 10-fold greater than that of JNK1. Thi s difference in c-Jun phosphorylation correlates with increased bindin g of c-Jun to JNK2 compared with JNK1. The distinct in vitro biochemic al properties of these JNK isoforms suggest that they may have differe nt functions in vivo. Evidence in favor of this hypothesis was obtaine d from the observation that JNK1, but not JNK2, complements a defect i n the expression of the mitogen-activated protein kinase HOG1 in the y east Saccharomyces cerevisiae. Together, these data indicate a role fo r the JNK group of protein kinases in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation.