The Integration of the Wnt and cAMP Signalling Pathways by AKAP220

Abstract

The cAMP‐responsive protein kinase PKA is a multifunctional enzyme with a broad range of substrates. Proteins designated A‐kinase anchoring proteins (AKAPs) coanchor PKA and substrates together to enhance PKA signalling specificity. Members of this family include MAP2 (microtubule‐associated protein 2), neuronally expressed AKAP79 and AKAP150, and the DNA binding AKAP95. AKAP220 is a less‐well characterized A‐kinase anchoring protein however, is known to anchor protein phosphatase 1 (PP1), PKA, and glycogen synthase kinase‐3 (GSK‐3). Furthermore, I have recently identified β‐catenin as an additional anchored protein. β‐catenin is a transcription factor central to the Wnt signalling pathway. In the absence of Wnt signalling, GSK‐3 can phosphorylate β‐catenin to direct its rapid proteasomal degradation. It has been shown previously by Tanji et al. (2002) JBC, that GSK‐3 anchored to AKAP220 is phosphorylated by PKA and that phosphorylation inactivates GSK‐3. I have shown that the downstream effector of GSK‐3, β‐catenin forms a complex with over expressed AKAP220 in HEK 293 cells. Additionally, endogenous AKAP220 and β‐catenin form a complex in rat H9C2 and PC12 cells. Cellular based assays also suggest that PKA can phosphorylate β‐catenin following stimulation with the adenylyl cyclase activator forskolin. Our recent evidence therefore suggests that AKAP220 may integrate the cAMP and Wnt signalling pathways. The integration of cAMP signalling and the Wnt pathway may play a critical role in processes like wound healing and in pathological conditions like cardiac hypertrophy, of which both pathways have been implicated. The work described will provide fundamental information regarding the integration of these important pathways.*This work is supported by National Institutes of Health grant DK54441.