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PAK4 Phosphorylates Fumarase and Blocks TGFβ-Induced Cell Growth Arrest in Lung Cancer Cells

Tao Chen1, Ting Wang2,3, Wenhua Liang1

  • 1State Key Laboratory of Respiratory Diseases; National Clinical Research Center of Respiratory Diseases; Guangzhou Institute of Respiratory Health; First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.

Cancer Research
|January 27, 2019
PubMed

Insights

Fumarase (FH) normally halts lung cancer cell growth by interacting with CSL and p53. However, PAK4-driven FH phosphorylation blocks this crucial tumor-suppressing mechanism in non-small cell lung cancer.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Fumarase (FH) metabolic activity influences gene transcription and tumor cell growth.
  • The role of FH in lung cancer pathogenesis is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which FH affects gene transcription and cell growth in lung cancer.
  • To investigate the role of specific phosphorylation events on FH in non-small cell lung cancer (NSCLC).

Main Methods:

  • Investigated TGFβ-induced FH phosphorylation at Thr 90 and its role in p21 transcription.
  • Examined the interaction of FH with CSL (RBP-Jκ) and p53.
  • Analyzed the effect of PAK4-mediated FH phosphorylation at Ser 46 in NSCLC cells.
  • Correlated FH phosphorylation status with patient prognosis.

Main Results:

  • TGFβ induces p38-mediated FH phosphorylation at Thr 90, promoting p21 transcription and cell growth arrest via a FH/CSL/p53 complex.
  • PAK4 phosphorylates FH at Ser 46 in NSCLC cells, leading to cytosolic detention and blocking the tumor-suppressive complex.
  • FH Ser 46 phosphorylation promotes tumorigenesis by inhibiting Thr 90 phosphorylation-mediated growth arrest.
  • Aberrant FH phosphorylation correlates with poor prognosis in lung cancer patients.

Conclusions:

  • FH plays a dual role in lung cancer, with its tumor-suppressive function being inhibited by PAK4-mediated phosphorylation.
  • Understanding FH phosphorylation provides novel insights into lung cancer development and potential therapeutic targets.

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