Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer

Mol Cell. 2019 Apr 18;74(2):378-392.e5. doi: 10.1016/j.molcel.2019.02.018. Epub 2019 Mar 20.

Abstract

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Here, we report that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. Cancer-associated hotspot mutations in the pseudosubstrate of PKCβ that impair autoinhibition result in dephosphorylated and unstable enzymes. Protein-level analysis reveals that PKCα is fully phosphorylated at the PHLPP site in over 5,000 patient tumors, with higher PKC levels correlating (1) inversely with PHLPP1 levels and (2) positively with improved survival in pancreatic adenocarcinoma. Thus, PHLPP1 provides a proofreading step that maintains the fidelity of PKC autoinhibition and reveals a prominent loss-of-function mechanism in cancer by suppressing the steady-state levels of PKC.

Keywords: PHLPP1; autoinhibition; cancer; degradation; loss of function; pancreatic cancer; phosphorylation; protein kinase C; quality control; reverse phase protein array.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Isoenzymes / genetics
  • Loss of Function Mutation / genetics
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Nuclear Proteins / genetics*
  • Phosphoprotein Phosphatases / genetics*
  • Phosphorylation
  • Protein Kinase C beta / genetics*
  • Protein Kinase C-alpha / genetics*
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / genetics
  • Quality Control
  • Signal Transduction / genetics

Substances

  • Isoenzymes
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-akt
  • PRKCA protein, human
  • PRKCB protein, human
  • Protein Kinase C beta
  • Protein Kinase C-alpha
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases