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FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4

Nami Sugiyama1, Markku Varjosalo, Pipsa Meller

  • 1Department of Pathology, Haartman Institute, University of Helsinki, Helsinki University Central Hospital, Finland.

Proceedings of the National Academy of Sciences of the United States of America
|August 28, 2010
PubMed

Insights

Tumor cells use membrane type 1 matrix metalloproteinase (MT1-MMP) for invasion. Kinase screening revealed an MT1-MMP/FGF receptor-4 (FGFR4) complex that impacts cancer progression based on FGFR4 genetic variants, affecting invasion and metastasis.

Area of Science:

  • Molecular oncology
  • Cellular signaling
  • Cancer metastasis

Background:

  • Tumor cell invasion and metastasis are critical processes in cancer progression.
  • Membrane type 1 matrix metalloproteinase (MT1-MMP) is crucial for tumor cell invasion.
  • Signaling pathways regulating MT1-MMP in cancer remain incompletely understood.

Purpose of the Study:

  • To identify kinases regulating MT1-MMP activity in tumor cells.
  • To elucidate the role of the MT1-MMP/FGFR4 complex in cancer invasion.
  • To investigate the impact of FGFR4 genetic variants on MT1-MMP function and cancer prognosis.

Main Methods:

  • Systematic gain-of-function kinome screen to identify MT1-MMP-activating kinases.
  • Analysis of MT1-MMP and FGF receptor-4 (FGFR4) interactions and signaling.
  • Investigation of tumor progression-associated FGFR4 polymorphisms (FGFR4-R388 and FGFR4-G388).
  • Assessment of MT1-MMP degradation, phosphorylation, and cell surface stabilization.

Main Results:

  • A novel MT1-MMP/FGFR4 membrane complex was identified.
  • The FGFR4-R388 allele, associated with poor prognosis, enhanced collagen invasion by reducing MT1-MMP lysosomal degradation.
  • FGFR4-R388 induced MT1-MMP phosphorylation and stabilization, leading to increased FGFR4-R388 autophosphorylation.
  • Phosphorylation-defective MT1-MMP stabilized on the cell surface induced FGFR4-R388 internalization and cell-cell junction dissociation.
  • The FGFR4-G388 variant down-regulated MT1-MMP, while MT1-MMP overexpression induced FGFR4-G388 degradation.

Conclusions:

  • MT1-MMP and FGFR4 form a complex whose activity is modulated by FGFR4 genetic variants.
  • The FGFR4-R388 allele promotes cancer invasion through MT1-MMP stabilization and altered degradation pathways.
  • These findings provide a mechanistic link between FGFR4 polymorphism, MT1-MMP regulation, and cancer invasion, offering potential therapeutic targets.

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