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FBXL5 targets cortactin for ubiquitination-mediated destruction to regulate gastric cancer cell migration

Gang Cen1, Hong-Hua Ding, Bin Liu

  • 1Department of General Surgery, The First People's Hospital Affiliated to Shanghai JiaoTong University, Shanghai, 200080, People's Republic of China.

Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
|May 29, 2014
PubMed

Insights

FBXL5 targets cortactin for degradation in gastric cancer, inhibiting cell migration. This process is regulated by extracellular signal-regulated kinase (ERK) and cortactin phosphorylation.

Area of Science:

  • Molecular biology
  • Cancer research
  • Cell biology

Background:

  • Cortactin is an actin-interacting protein crucial for cytoskeletal dynamics.
  • Cortactin amplification is observed in various cancers, including gastric adenocarcinomas.
  • Reduced cortactin levels impede cancer cell migration and invasion.

Purpose of the Study:

  • To investigate the regulatory mechanisms of cortactin in gastric cancer.
  • To identify proteins that interact with and degrade cortactin.
  • To elucidate the role of FBXL5 in cortactin regulation and its impact on gastric cancer cell migration.

Main Methods:

  • Co-immunoprecipitation assays to identify protein interactions.
  • Ubiquitylation assays to assess protein degradation pathways.
  • Western blotting to detect protein levels and phosphorylation status.
  • Site-directed mutagenesis to study specific phosphorylation sites (S405/S418) on cortactin.
  • Cell migration assays to evaluate the functional impact of cortactin regulation.

Main Results:

  • FBXL5 directly interacts with cortactin and targets it for ubiquitylation and proteasomal degradation.
  • Extracellular signal-regulated kinase (ERK) mediates FBXL5-induced cortactin degradation.
  • Mutating serine phosphorylation sites (S405/S418) on cortactin prevents FBXL5-mediated degradation.
  • The phosphorylation-resistant cortactin mutant (cortactinS405A/S418A) enhances gastric cancer cell migration more than wild-type cortactin.

Conclusions:

  • FBXL5 acts as a negative regulator of cortactin in gastric cancer cells.
  • The FBXL5-ERK-cortactin axis represents a novel mechanism controlling cortactin stability and gastric cancer cell migration.
  • Targeting the FBXL5-mediated degradation pathway could offer therapeutic strategies for gastric cancer.

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