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MT1-MMP regulates VEGF-A expression through a complex with VEGFR-2 and Src

Patricia A Eisenach1, Christian Roghi, Marton Fogarasi

  • 1University of Cambridge, Department of Oncology, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

Journal of Cell Science
|November 11, 2010
PubMed

Insights

Membrane-type-1 matrix metalloproteinase (MT1-MMP) regulates VEGF-A transcription in breast cancer. This involves a complex with VEGFR-2 and Src, impacting cell signaling and tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Membrane-type-1 matrix metalloproteinase (MT1-MMP) is crucial for cancer cell migration and invasion.
  • Elevated MT1-MMP levels indicate a poor cancer prognosis.
  • The precise mechanisms of MT1-MMP's transcriptional regulation in cancer are not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which MT1-MMP regulates VEGF-A expression in breast cancer cells.
  • To investigate the role of MT1-MMP in cell surface localization of VEGFR-2.
  • To identify the specific domains and activities of MT1-MMP involved in VEGF-A transcription.

Main Methods:

  • Investigated MT1-MMP's interaction with VEGFR-2 and Src in breast cancer cells.
  • Assessed the dependency of complex formation and VEGFR-2 localization on MT1-MMP domains and activity.
  • Analyzed the downstream signaling cascade, including Akt and mTOR activation, leading to VEGF-A transcription.

Main Results:

  • MT1-MMP forms a complex with VEGFR-2 and Src, dependent on its hemopexin domain but independent of its catalytic activity.
  • VEGFR-2 cell surface localization is independent of MT1-MMP's catalytic and intracellular domains.
  • VEGF-A transcription requires MT1-MMP's catalytic and intracellular domains, with functional redundancy from MMP-2 or MMP-7.
  • The MT1-MMP-VEGFR-2-Src complex activates Akt and mTOR, promoting VEGF-A transcription.

Conclusions:

  • MT1-MMP plays a critical role in regulating VEGF-A transcription through a complex involving VEGFR-2 and Src.
  • Both the hemopexin domain and catalytic activity of MT1-MMP are essential for this process, albeit through distinct mechanisms.
  • This pathway contributes to tumor growth by increasing VEGF-A expression in breast cancer.

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