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Updated: Sep 18, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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PTEN protein phosphatase activity regulates metastasis by targeting PKCδ

Yanlin Yu1, Ming Zhao2, Rand Gabriel M Buenaventura1

  • 1Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Iscience
|June 23, 2025
PubMed

Insights

The tumor suppressor PTEN inhibits cancer metastasis by dephosphorylating PKCδ. This protein phosphatase activity is crucial for PTEN

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • PTEN is a critical tumor suppressor involved in cell signaling.
  • PTEN possesses both lipid and protein phosphatase activities.
  • Previous research indicated PTEN inhibits metastasis independently of its lipid phosphatase function.

Purpose of the Study:

  • To identify downstream substrates of PTEN protein phosphatase activity.
  • To elucidate the role of these substrates in PTEN-mediated metastatic suppression.

Main Methods:

  • Proteomic approaches were utilized to identify PTEN protein phosphatase substrates.
  • Knock-in and knock-out models were established to validate findings.
  • Analysis of PKCδ phosphorylation at specific sites (S643, T505, Y311).

Main Results:

  • PKCδ was identified as a direct substrate of PTEN protein phosphatase.
  • Inactivation of PTEN protein phosphatase activity prevented PKCδ dephosphorylation.
  • PTEN protein phosphatase activity is essential for inhibiting PKCδ phosphorylation and suppressing tumor metastasis.

Conclusions:

  • PTEN's metastasis suppressor function is directly linked to its protein phosphatase activity targeting PKCδ.
  • PKCδ promotes melanoma metastasis, and its phosphorylation is regulated by PTEN.
  • Targeting the PTEN-PKCδ axis may offer therapeutic strategies for metastatic melanoma.
Keywords:
Proteomicscancer

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