Eisenach, Patricia A., Roghi, Christian, Fogarasi, Marton, Murphy, Gillian and English, William R. ORCID: https://orcid.org/0000-0003-3024-2441
(2010)
MT1-MMP regulates VEGF-A expression through a complex with VEGFR-2 and Src.
Journal of Cell Science, 123 (23).
pp. 4182-4193.
ISSN 0021-9533
Abstract
Membrane-type-1 matrix metalloproteinase (MT1-MMP) is a zinc-dependent type-I transmembrane metalloproteinase involved in pericellular proteolysis, migration and invasion, with elevated levels correlating with a poor prognosis in cancer. MT1-MMP-mediated transcriptional regulation of genes in cancer cells can contribute to tumour growth, although this is poorly understood at a mechanistic level. In this study, we investigated the mechanism by which MT1-MMP regulates the expression of VEGF-A in breast cancer cells. We discovered that MT1-MMP regulates VEGFR-2 cell surface localisation and forms a complex with VEGFR-2 and Src that is dependent on the MT1-MMP hemopexin domain and independent of its catalytic activity. Although the localisation of VEGFR-2 was independent of the catalytic and intracellular domain of MT1-MMP, intracellular signalling dependent on VEGFR-2 activity leading to VEGF-A transcription still required the MT1-MMP catalytic and intracellular domain, including residues Y573, C574 and DKV582. However, there was redundancy in the function of the catalytic activity of MT1-MMP, as this could be substituted with MMP-2 or MMP-7 in cells expressing inactive MT1-MMP. The signalling cascade dependent on the MT1-MMP-VEGFR-2-Src complex activated Akt and mTOR, ultimately leading to increased VEGF-A transcription.
Item Type: | Article |
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Uncontrolled Keywords: | sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
Faculty \ School: | Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School |
UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
Depositing User: | LivePure Connector |
Date Deposited: | 15 Dec 2022 11:31 |
Last Modified: | 19 Oct 2023 03:30 |
URI: | https://ueaeprints.uea.ac.uk/id/eprint/90211 |
DOI: | 10.1242/jcs.062711 |
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