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

Timothy R. Baffi, An Angela N. Van, Wei Zhao, Gordon Mills, Alexandra C. Newton

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)378-392.e5
JournalMolecular Cell
Volume74
Issue number2
DOIs
StatePublished - Apr 18 2019
Externally publishedYes

Fingerprint

Phosphoric Monoester Hydrolases
Quality Control
Protein Kinase C
Neoplasms
Phosphorylation
Second Messenger Systems
Enzymes
Isoenzymes
Adenocarcinoma
Phosphotransferases
Mutation
Survival
Proteins

Keywords

  • autoinhibition
  • cancer
  • degradation
  • loss of function
  • pancreatic cancer
  • PHLPP1
  • phosphorylation
  • protein kinase C
  • quality control
  • reverse phase protein array

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer. / Baffi, Timothy R.; Van, An Angela N.; Zhao, Wei; Mills, Gordon; Newton, Alexandra C.

In: Molecular Cell, Vol. 74, No. 2, 18.04.2019, p. 378-392.e5.

Research output: Contribution to journalArticle

Baffi, Timothy R. ; Van, An Angela N. ; Zhao, Wei ; Mills, Gordon ; Newton, Alexandra C. / Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer. In: Molecular Cell. 2019 ; Vol. 74, No. 2. pp. 378-392.e5.
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