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Published on: August 3, 2018
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
Summary
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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