Date Published: July 25, 2017
Publisher: Public Library of Science
Author(s): Kristoffer Søberg, Line Victoria Moen, Bjørn Steen Skålhegg, Jon Kristen Laerdahl, Narayanaswamy Srinivasan.
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 Cα and Cβ, 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 Cα1/Cβ1 isoforms, we find kinase variants with short N-termini in all main vertebrate classes, including the sperm-specific Cα2 isoform found to be conserved in all mammals. We also describe, for the first time, a PKA Cα isoform with a long N-terminus, paralogous to the PKA Cβ2 N-terminus. An analysis of isoform-specific variation highlights residues and motifs that are likely to be of functional importance.
The protein kinase (PK) gene family is one of the largest in the human genome, comprising over 500 different PK encoding genes . PKs catalyze the transfer of phosphate groups onto Ser, Thr, or Tyr residues of target proteins. Phosphorylation of substrates represents a key regulatory mechanism in all eukaryotic cells , and the various PKs target different substrates with a multitude of biological effects. 3’,5’-cyclic adenosine monophosphate (cAMP)-dependent protein kinase, or protein kinase A (PKA), is among the best studied PKs. It has been used as a model kinase for all PKs, and several thousand articles and over a hundred different crystal structures of PKA have been published, emphasizing its key role in PK and signal transduction research.
Orthologs of human PRKACA and PRKACB were obtained from the preclustered gene data available in Ensembl  and from the NCBI RefSeq and non-redundant database resources [59, 60] employing standard BLAST  sequence searching.