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A-Kinase Anchoring Proteins and Regulation of Nuclear Transport and Gene Expression

Chris Eggers

Appointment Period: 2003-2004 / Grant Year: [19]

Chris EggersThe RI regulatory subunit of the cAMP-dependent protein kinase (PKA) is overexpressed in many forms of cancer, including breast cancer, where it is linked to proliferation, malignant transformation, and poor prognosis. Inhibiting RI has been shown to slow cell proliferation and tumor growth. The targets of PKA are largely determined by its anchoring to specific locations in the cell by AKAPs, the A-Kinase Anchoring Proteins. These scaffolding proteins bind not only PKA, but often multiple other signaling proteins and potential substrates. Whereas the vast majority of AKAPs bind tightly to only the RII regulatory subunit, a subset of AKAPs including D-AKAP2 are considered “dual-specificity” because they can anchor both types of PKA. D-AKAP2 contains two RGS-like domains, as well as a C-terminal PDZ domain. RGS proteins traditionally interact with heterotrimeric G proteins, but we have been unable to demonstrate any interaction with any of the various subfamilies of G proteins. We have therefore searched for interacting partners for the first RGS domain by using a yeast two-hybrid screen. One putative partner we found is the gamma subunit of the AP-1 complex, which is involved in trafficking of clathrin-coated vesicles, a result that is consistent with another group’s finding that D-AKAP2 is present in complexes with the sodium-phosphate cotransporter, whose activity is controlled by trafficking. Another candidate to emerge is exportin 7, which is responsible for removing specific cargo proteins from the nucleus. We are continuing with both in vitro and cell-based studies to further elucidate the function of D-AKAP2. Our results highlight the possibilities of novel therapeutic approaches that would disrupt specific scaffolding interactions.

Eggers CT, Schafer JC, Goldenring JR, Taylor SS. D-AKAP2 interacts with Rab4 and Rab11 through its RGS domains and regulates transferrin receptor recycling. J Biol Chem. (2009) 284:32869-80. PMID: 19797056; PMCID: PMC2781703.