Regulation of JNK-signaling molecules by the gep oncogenes

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DESCRIPTION (provided by applicant): Ovarian cancer is identified as the fifth leading cause of cancer death in the United States with approximately 16,000 deaths every year. Although major advances have been made in understanding the pathology of this disease, 52 % of patients die because of the aggressive growth of these cancers. It has been recently observed that the lipid growth factor lysophosphatidic acid (LPA) promotes ovarian cancer genesis and progression. Our recent studies have shown that LPA-mediated oncogenic signaling involves the gep oncogenes, defined by the activated mutants of G?12 and G?13, that differentially regulate a number of MAP kinases including Jun N-terminal kinase (JNK). These MAPKs, in turn, elicit a multitude of cellular responses required for different physiological stimuli. The signaling complexity and precision of G?12/13 indicates the possible involvement of a scaffolding protein that can modulate specific signaling responses. Recently we have shown that these gep oncogenes, upon stimulation with LPA, interact with a scaffolding protein involved in the activation of JNKs (Kashef et al., 2005). This novel scaffolding protein known as JNK-interacting Leucine- zipper Protein (JLP) potentiates the activation of JNK by G?12/13. In addition, our studies indicate that JLP also tethers ?-PIX, a Rac/CDC42-specific guanine nucleotide exchange factor, to G?12/13 through which the JNK-module can be activated. Based on these results, we hypothesize that G?12/13-JLP interaction is critically involved in G?12/13-mediated activation of diverse cellular responses. In this application, we propose to test this hypothesis under the following specific aims: Aim 1: Characterization of G?13-JLP-?-PIX interaction through site-directed mutagenesis; Aim 2: Analysis of the interrelationship of G?13, JLP, and ?-PIX in forming a signaling complex; Aim 3: Defining the role of JLP on the oncogenic activity of G?12/13 and Aim 4: defining the Role of JLP- G?12/13 signaling in ovarian cancer genesis and progression. In addition to characterizing the etiological factors involved in the progression of ovarian cancer, the outcome of these studies is expected to identify novel therapeutic targets for the treatment of the disease.