Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites.
Protein Kinase C (PKC) is a family of serine/threonine kinases whose function is influenced by phosphorylation. In particular, three conserved phosphorylation sites known as the activation-loop, the turn-motif and the hydrophobic-motif play important roles in controlling the catalytic activity, stability and intracellular localisation of the enzyme. Prevailing models of PKC phosphorylation suggest that phosphorylation of these sites occurs shortly following synthesis and that these modifications are required for the processing of newly-transcribed PKC to the mature (but still inactive) form; phosphorylation is therefore a priming event that enables catalytic activation in response to lipid second messengers. However, many studies have also demonstrated inducible phosphorylation of PKC isoforms at these sites following stimulation, highlighting that our understanding of PKC phosphorylation and its impact on enzymatic function is incomplete. Furthermore, inducible phosphorylation at these sites is often interpreted as catalytic activation, which could be misleading for some isoforms. Recent studies that include systems-wide phosphoproteomic profiling of cells has revealed a host of additional (and in many cases non-conserved) phosphorylation sites on PKC family members that influence their function. Many of these may in fact be more suitable than previously described sites as surrogate markers of catalytic activation. Here we discuss the role of phosphorylation in controlling PKC function and outline our current understanding of the mechanisms that regulate these phosphorylation sites.
Freeley
Michael
M
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College, Dublin, Ireland. freeleym@tcd.ie
Kelleher
Dermot
D
Long
Aideen
A
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
D007527:Isoenzymes; D011493:Protein Kinase C