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Phosphorylation of FOXP3 by LCK downregulates MMP9 expression and represses cell invasion

Kumiko Nakahira1, Akihiro Morita, Nam-Soon Kim

  • 1Department of Developmental Medicine, Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi, Osaka, Japan.

Plos One
|October 25, 2013
PubMed

Insights

Lymphocyte-specific protein tyrosine kinase (LCK) upregulates Forkhead Box P3 (FOXP3) via tyrosine phosphorylation. This interaction suppresses cancer malignancy by reducing MMP9, SKP2, and VEGF-A expression and inhibiting cellular invasion.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Forkhead Box P3 (FOXP3) is a transcription factor crucial for T-regulatory cells and acts as a tumor suppressor.
  • Cancer malignancy is associated with lymphocyte-specific protein tyrosine kinase (LCK).
  • The interaction between FOXP3 and LCK in cancer is not well understood.

Purpose of the Study:

  • To investigate the relationship between FOXP3 and LCK in the context of cancer malignancy.
  • To elucidate the mechanism by which LCK affects FOXP3 activity and downstream targets.
  • To determine the role of LCK-mediated phosphorylation of FOXP3 in regulating cancer-associated genes and invasion.

Main Methods:

  • Identification of LCK as a binding partner of FOXP3.
  • Immunoprecipitation and in vitro kinase assays to confirm LCK phosphorylation of FOXP3 at Tyr-342.
  • Functional assays using wild-type FOXP3 and a Y342F mutant to assess effects on MMP9, SKP2, VEGF-A expression, and cellular invasion in MCF-7 cells.

Main Results:

  • LCK was identified as a binding partner of FOXP3.
  • LCK phosphorylates FOXP3 at Tyr-342, which is essential for FOXP3's ability to suppress MMP9 expression and cellular invasion.
  • LCK-induced upregulation of FOXP3 leads to decreased expression of MMP9, SKP2, and VEGF-A, and suppressed cellular invasion.

Conclusions:

  • LCK upregulates FOXP3 through tyrosine phosphorylation at Tyr-342.
  • This LCK-FOXP3 interaction suppresses key genes (MMP9, SKP2, VEGF-A) involved in cancer malignancy and reduces cellular invasion.
  • Understanding this mechanism offers potential for novel therapeutic strategies against cancer.

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