An emerging theme in cellular organization is that for many metabolic pathways, cells utilize large, multi-enzyme complexes that are recruited to specific subcellular sites through protein-protein interactions. Complex formation may play an important role in cellular signal transduction pathways as a means to target the activities of signaling enzymes and ensure an appropriate cellular response to a given stimulus. Many signaling cascades ultimately converge in the cell nucleus and the objective of this project is to characterize proteins that recruit signaling enzymes at the nuclear matrix. Using in-vitro approaches and experiments with cultured cells, we will investigate the cellular function of AKAP95, a novel anchoring protein for the cAMP-dependent protein kinase (PKA) that localizes to the nuclear matrix.
The specific aims of this proposal will test the hypothesis that AKAP95 plays a critical role in recruiting PKA to initiation complexes involved in hormone-induced gene expression. We will also investigate nuclear anchoring of other signaling enzymes by NAKAP95. a newly discovered protein that is related to AKAP95 but does not bind PKA. Using novel inhibitor peptides and expression systems, we will determine the functional effect of disrupting anchoring protein-mediated targeting on the transcription of specific genes. These studies have particular relevance to cancer, as malignant progression is accompanied by changes in nuclear organization, gene expression, and the control of cellular signaling pathways.
| Sayer, Jonathan A; Manczak, Maria; Akileswaran, Lakshmi et al. (2005) Interaction of the nuclear matrix protein NAKAP with HypA and Huntingtin: implications for nuclear toxicity in Huntington's disease pathogenesis. Neuromolecular Med 7:297-310 |
