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The activated mutants of the α-subunits of G proteins G12 and G13 have been designated as the gep oncogenes owing to their ability to stimulate diverse oncogenic signaling pathways that lead to neoplastic transformation of fibroblast cell lines and tumorigenesis in nude mice models. Studies from our laboratory as well as others have shown that the growth-promoting activities of Gα12 and Gα13 involve potent activation of c-Jun N-terminal kinases (JNKs). Our previous studies have indicated that the JNK-interacting leucine zipper protein (JLP), a scaffold protein involved in the structural and functional organization of the JNK/p38 mitogen-activated protein kinase module, tethers Gα12 and Gα13 to the JNK signaling module. In the present study, in addition to demonstrating the physical association between JLP and Gα12, we show that this interaction is enhanced by the receptor- or mutation-mediated activation of Gα12. We also establish that JLP interacts with Gα12 through the C-terminal domain that has been previously identified to be involved in binding to Gα13. Furthermore, using this C-terminal domain as a competitively inhibitor of JLP that can disrupt Gα12-JLP interaction, we demonstrate that JLP is required for the stimulation of JNK by Gα12. Our results also indicate that such JLP interaction is required for Gα12 as well as Gα13-mediated neoplastic transformation of JLP. These studies demonstrate for the first time a functional role for JLP in the gep oncogene-regulated neoplastic signaling pathway.