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Updated: Jun 21, 2025

Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis
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Stearoylation cycle regulates the cell surface distribution of the PCP protein Vangl2

Jiafu Ying1,2, Yinghong Yang1,2, Xuanpu Zhang1,2

  • 1Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.

Proceedings of the National Academy of Sciences of the United States of America
|July 10, 2024
PubMed

Insights

Planar cell polarity (PCP) protein Vangl2 is regulated by S-stearoylation, a reversible fatty acylation process. This lipid modification is crucial for Vangl2 localization, cell migration, and preventing cancer progression.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Planar cell polarity (PCP) pathway defects are linked to human diseases, including neural tube defects and cancer.
  • Vangl2 is a key protein in PCP signaling, but its post-translational regulation remains unclear.

Purpose of the Study:

  • To investigate the post-translational regulation of Vangl2.
  • To elucidate the role of fatty acylation in Vangl2 function and its implications in disease.

Main Methods:

  • Utilized chemical reporters for fatty acylation and biochemical validation.
  • Generated and analyzed stearoylation-deficient Vangl2 mutants.
  • Assessed Vangl2 plasma membrane localization and PCP establishment during cell migration.
  • Investigated the impact of Vangl2 stearoylation on oncogenic signaling pathways (YAP, AKT, ERK) and cancer cell growth.

Main Results:

  • Vangl2 subcellular localization is controlled by a reversible S-stearoylation cycle, primarily regulated by ZDHHC9 and APT1.
  • A stearoylation-deficient Vangl2 mutant exhibited reduced plasma membrane localization, disrupting PCP.
  • Inhibition of ZDHHC9 mimicked the effects of Vangl2 stearoylation loss.
  • Loss of Vangl2 stearoylation promoted oncogenic signaling and breast cancer cell growth.

Conclusions:

  • Vangl2 is regulated by S-stearoylation, a critical mechanism for its localization and PCP establishment.
  • This lipidation process influences tumorigenesis by modulating YAP, AKT, and ERK signaling.
  • Fatty acid metabolism and protein acylation are key regulators of PCP signaling and cancer development.
Keywords:
Vangl2click chemistryplanar cell polarityprotein lipidationstearoylation

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