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Peptidyl-prolyl isomerase Pin1 controls down-regulation of conventional protein kinase C isozymes

Hilde Abrahamsen1, Audrey K O'Neill, Natarajan Kannan

  • 1Department of Pharmacology, Graduate Program, University of California, San Diego, La Jolla, California 92093, USA.

The Journal of Biological Chemistry
|February 10, 2012
PubMed

Insights

The peptidyl-prolyl isomerase Pin1 acts as a timer for protein kinase C (PKC) enzyme lifespan. Pin1 converts activated PKC into a form that can be degraded, regulating its cellular levels.

Area of Science:

  • Cellular signaling
  • Enzymology
  • Molecular biology

Background:

  • Protein kinase C (PKC) isozymes are crucial signaling enzymes.
  • Prolonged activation by phorbol esters leads to PKC down-regulation, but the mechanism is unclear.
  • It is unknown if physiological agonists also induce PKC down-regulation.

Purpose of the Study:

  • To elucidate the mechanism of protein kinase C (PKC) down-regulation.
  • To investigate the role of peptidyl-prolyl isomerase Pin1 in regulating PKC lifespan.
  • To determine if Pin1-mediated regulation occurs following stimulation by physiological agonists.

Main Methods:

  • Investigated the interaction between Pin1 and conventional PKC isozymes.
  • Assessed the requirement of Pin1's catalytic activity and specific phosphorylation sites on PKC.
  • Utilized phorbol esters and natural agonists to induce PKC activation.

Main Results:

  • Pin1 acts as a timer for conventional PKC isozymes' lifespan.
  • Pin1 converts activated PKC into a species that undergoes dephosphorylation and ubiquitination.
  • Pin1 regulation requires its catalytic activity and a specific phospho-Thr-Pro motif on PKC.
  • The hydrophobic motif of PKC docks Pin1, facilitating the isomerization of the phospho-Thr-Pro bond.

Conclusions:

  • Pin1 is essential for the down-regulation of conventional PKC isozymes following activation.
  • Pin1-mediated isomerization of the phospho-Thr-Pro bond at the turn motif converts PKC into a degradable form.
  • This mechanism explains PKC down-regulation induced by both phorbol esters and physiological agonists.

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