Neoplastic Transformation Induced by the gep Oncogenes Involves the Scaffold Protein JNK-Interacting Leucine Zipper Protein

作者：Kashef Kimia; Radhakrishnan Rangasudhagar; Lee Clement M; Reddy E Premkumar; Dhanasekaran Danny N^*

来源：Neoplasia, 2011, 13(4): 358-364.

DOI：10.1593/neo.101622

The activated mutants of the alpha-subunits of G proteins G(12) and G(13) 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 G alpha(12) and G alpha(13) 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 G alpha(12) and G alpha(13) to the JNK signaling module. In the present study, in addition to demonstrating the physical association between JLP and G alpha(12), we show that this interaction is enhanced by the receptor-or mutation-mediated activation of G alpha(12). We also establish that JLP interacts with G alpha(12) through the C-terminal domain that has been previously identified to be involved in binding to G alpha(13). Furthermore, using this C-terminal domain as a competitively inhibitor of JLP that can disrupt G alpha(12)-JLP interaction, we demonstrate that JLP is required for the stimulation of JNK by G alpha(12). Our results also indicate that such JLP interaction is required for G alpha(12) as well as G alpha(13)-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.

• 出版日期2011-4