The role of C2 domains in PKC signaling

Adv Exp Med Biol. 2012:740:663-83. doi: 10.1007/978-94-007-2888-2_29.


More than two decades ago, the discovery of the first C2 domain in conventional Protein Kinase Cs (cPKCs) and of its role as a calcium-binding motif began to shed light on the activation mechanism of this family of Serine/Threonine kinases which are involved in several critical signal transduction pathways. In this chapter, we review the current knowledge of the structure and the function of the different C2 domains in PKCs. The C2 domain of cPKCs is a calcium sensor and its calcium-dependent binding to phospholipids is crucial for kinase activation. While the functional role of the cPKC C2 domain is better understood, phylogenetic analysis revealed that the novel C2 domain is more ancient and related to the C2 domain in the fungal PKC family, while the cPKC C2 domain is first associated with PKC in metazoans. The C2 domain of novel PKCs (nPKCs) does not contain a calcium-binding motif but still plays a critical role in nPKCs activation by regulating C1-C2 domain interactions and consequently C2 domain-mediated inhibition in both the nPKCs of the epsilon family and the nPKCs of the delta family. Moreover, the C2 domain of the nPKCs of the delta family was shown to recognize phosphotyrosines in a novel mode different from the ones observed for the Src Homology 2 (SH2) and the phosphotyrosine binding domains (PTB). By binding to phosphotyrosines, the C2 domain regulates the activation of this subclass of PKCs. The C2 domain was also shown to be involved in protein-protein interactions and binding to the receptor for activated C-kinase (RACKs) thus contributing to the subcellular localization of PKCs. In summary, the C2 domain is a critical player that can sense the activated signaling pathway in response to external stimuli to specifically regulate the different conventional and novel PKC isoforms.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism
  • Evolution, Molecular
  • Humans
  • Molecular Sequence Data
  • Phospholipids / metabolism
  • Protein Kinase C / chemistry
  • Protein Kinase C / physiology*
  • Protein Structure, Tertiary
  • Signal Transduction


  • Phospholipids
  • Protein Kinase C
  • Calcium