Oncogenic effect of delta deletion in v-Jun does not result from uncoupling Jun from JNK signaling

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Abstract
The protein encoded by the v-Jun oncogene shows increased transforming activity compared to c-Jun, its normal cellular counterpart. One major determinant of this increased transforming activity is an in-frame deletion of a region near the amino-terminus of the protein. This region, referred to as the delta domain, functions as a docking site for Jun N-terminal kinase (JNK), the mitogen-activated protein (MAP) kinase that phosphorylates c-Jun to regulate its transcriptional properties. As a consequence of this deletion, v-Jun is unresponsive to JNK signaling, and it is widely believed that it is the uncoupling of v-Jun from JNK signaling that underlies the oncogenic effects of the delta-domain deletion; however, this idea has never been directly tested. Here we use JNK overexpression as well as alanine scanning mutagenesis to test this idea. Point mutants that are uncoupled from JNK signaling do not show enhanced transforming activity, suggesting that disruption of the Jun-JNK interaction is not the mechanism by which the delta-domain deletion enhances transforming activity. Consistent with this idea, we have generated a panel of point mutants that show markedly enhanced transforming activity, despite the fact that they do not perturb the ability of JNK to either dock with or phosphorylate c-Jun in vitro or in vivo. The fact that these mutants cluster in a small region suggests the existence of an additional regulator of Jun function whose activity is disrupted by mutations in this region.