Constitutive activation of the 41-/43-kDa mitogen-activated protein kinasesignaling pathway in human tumors

The 41-kDa and 43-kDa mitogen-activated protein (MAP) kinases play a pivota l role in the mitogenic signal transduction pathway and are essential compo nents of the MAP kinase cascade, which includes MAP kinase kinase (MEK) and Raf-l, As aberrant activation of signal transducing molecules such as Pas and Raf-l has been linked with cancer, we examined whether constitutive act ivation of the 41-/43-kDa MAP kinases is associated with the neoplastic phe notype of 138 tumor cell lines and 102 primary tumors derived from various human organs. Constitutive activation of the MAP kinases was observed in 50 tumor cell lines (36.2%) in a rather tissue-specific manner: cell lines de rived from pancreas, colon, lung, ovary and kidney showed especially high f requencies with a high degree of MAP kinase activation, while those derived from brain, esophagus, stomach, liver and of hematopoietic origin showed l ow frequencies with a limited degree of MAP kinase activation. We also dete cted constitutive activation of the 41-/43-kDa MAP kinases in a relatively large number of primary human tumors derived from kidney, colon and lung ti ssues but not from liver tissue. Many tumor cells, in which point mutations of vas genes mere detected, showed constitutive activation of MAP kinases, however, there were also many exceptions to this observation. In contrast, the activation of the 41-/43-kDa MAP kinases was accompanied by the activa tion of Raf-l in the majority of tumor cells and was completely associated with the activation of MEK and p90(rsk) in all the tumor cells examined, Th ese results suggest that the constitutive activation of 41-/43-kDa MAP kina ses in tumor cells is not due to the disorder of MAP kinases themselves, bu t is due to the disorder of Raf-l, Pas, or some other signaling molecules u pstream of Ras.