Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms

The 3', 5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, or protein kinase A (PKA), pathway is one of the most versatile and best studied signaling pathways in eukaryotic cells. The two paralogous PKA catalytic subunits C alpha and C beta, encoded by the genes PRKACA and PRKACB, respectively, are among the best understood model kinases in signal transduction research. In this work, we explore and elucidate the evolution of the alternative 5' exons and the splicing pattern giving rise to the numerous PKA catalytic subunit isoforms. In addition to the universally conserved C alpha 1/C beta 1 isoforms, we find kinase variants with short N-termini in all main vertebrate classes, including the sperm-specific C alpha 2 isoform found to be conserved in all mammals. We also describe, for the first time, a PKA C alpha isoform with a long N-terminus, paralogous to the PKA C beta 2 N-terminus. An analysis of isoform-specific variation highlights residues and motifs that are likely to be of functional importance.