Fifty Years Since the Discovery of PKA

In 1968, after Sutherland's discovery of cAMP, Krebs discovered cAMP‐dependent Protein Kinase (PKA), thus establishing the major paradigm for cAMP signaling in mammalian cells. The protein kinases, one of the largest gene families, are associated with many diseases, and PKA serves as a prototype for general protein kinase structure and function. While the structure of PKA first defined the conserved protein kinase fold, the recent solution of inhibited complexes of the catalytic (C) and regulatory (R) subunits have defined not only the molecular basis for inhibition but also the mechanisms for activation by cAMP. In addition, they show the dramatic flexibility that is embedded within the R‐subunit as it releases cAMP and wraps itself around the large lobe of the C‐subunit. In contrast, the C‐subunit functions as a stable scaffold that binds to many proteins. In addition to the R‐subunit isoforms and PKI, the C‐subunit docks to other proteins such as the A K inase I nteracting P rotein (AKIP‐1), which contributes to its nuclear localization. The R‐ and C‐subunits do not typically exist as isolated entities in the cell but instead are part of large complexes assembled in part through A K inase A nchoring P roteins (AKAPs). Localization and trafficking are an essential part of kinase function, and the challenge for the next decade will be to understand how these large PKA‐mediated signaling complexes assemble and integrate highly regulated functional responses. It is a challenge that requires the concerted integration of structural biology, cell biology, pharmacology and physiology. (Funded by grants from the NIH to SST and fellowships from the American Cancer Society to CK and CWE, and NIH Training Grant GM08326 to CYC.)