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ALK phosphorylates SMAD4 on tyrosine to disable TGF-β tumour suppressor functions

Qianting Zhang1, Mu Xiao1, Shuchen Gu1

  • 1MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.

Nature Cell Biology
|January 22, 2019
PubMed

Insights

Transforming growth factor beta (TGF-β) resistance in ALK-positive cancers occurs when ALK phosphorylates SMAD4, blocking its tumor-suppressing function. Restoring TGF-β signaling via ALK inhibition offers a targeted therapy approach.

Area of Science:

  • Oncology
  • Molecular Biology
  • Signal Transduction

Background:

  • Loss of TGF-β tumor-suppressive response is a hallmark of human cancers.
  • SMAD4, a key player in TGF-β signaling, is often altered in gastrointestinal and pancreatic cancers, but mechanisms of resistance in other cancer types remain unclear.
  • ALK-positive tumors, including lymphoma, lung cancer, and neuroblastoma, exhibit resistance to TGF-β signaling.

Purpose of the Study:

  • To elucidate the mechanism of TGF-β resistance in ALK-positive tumors.
  • To investigate the role of ALK in SMAD4 regulation and TGF-β signaling.
  • To identify potential therapeutic strategies targeting ALK-positive cancers.

Main Methods:

  • Investigated ALK-positive tumor cell lines (lymphoma, lung cancer, neuroblastoma).
  • Utilized biochemical assays to examine ALK-mediated phosphorylation of SMAD4.
  • Assessed the impact of SMAD4 phosphorylation on DNA binding and gene expression.
  • Evaluated the efficacy of chemical and genetic ALK inhibition in restoring TGF-β responses.

Main Results:

  • ALK directly phosphorylates SMAD4 at Tyrosine 95 (Tyr95) in ALK-positive tumors.
  • Phosphorylated SMAD4 is impaired in DNA binding, leading to the loss of TGF-β-mediated gene responses and tumor suppression.
  • Interference with oncogenic ALK (chemically or genetically) restores SMAD4 function and TGF-β responses in these cancer cells.

Conclusions:

  • SMAD4 inactivation occurs through tyrosine phosphorylation by the oncogenic ALK kinase in ALK-positive cancers.
  • This mechanism explains TGF-β resistance in these tumor types.
  • Targeting ALK offers a promising therapeutic strategy for ALK-positive cancers exhibiting SMAD4-mediated TGF-β resistance.

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