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led to a better understanding of both the complexity and the subtlety of PKA signaling, and point the way for future studies, which may help of recent analysis of all human protein kinases terotrimeric ptors couple t dissociation ociate with Cs), which cAMP binds e and induc-(Fig. 1). that the PKA holoenzyme is comprised of four subunits, two of which are catalytically active to regulate hen bound together, the heterotetrameric enzyme is inactive. eratively to paired binding pockets on each of the Endocrine-Related Cancer (2009) 16 773–793in many forms of intercellular communication. Afterliganding of the receptor, a conformational change is transcription, a function mapped to PKA’s ability to(Manning et al. 2002). In canonical PKA signaling, extracellular hormones bind to G-protein coupled receptors, a large family of seven transmembrane domain proteins involved regulatory subunits, causing release of free, catalyti-cally active, PKAC monomers. Initial studies revealed that manipulation of PKA activity produced changes in the activity of protein substrates (e.g. phosphorylase kinase (Walsh et al. 1968)), but also changes in genethrough protein phosphorylation, and the character-ization of this enzyme can be thought to lie at the ‘root’ However, when cAMP levels within the cell rise in response to membrane signaling, cAMP binds coop-Medicine, to Sutherland (in 1971) and subsequently to Gilman & Rodbell (in 1994). Studies of PKA have formed the basis of signal transduction mediated (PKAC subunits), and two of each serve enzyme activity (PKAR subunits). Wprovided the basis for two Nobel prize awards inWalsh et al. 1968). These observations formed the basis for understanding hormonal signaling, and Through early characterization, it was determinedEndocrine-Related Cancer (2009) 16 773–79