MT1-MMP regulates VEGF-A expression through a complex with VEGFR-2 and Src.
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.
University of Cambridge, Department of Oncology, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Patricia A
PA
Eisenach
Christian
C
Roghi
Marton
M
Fogarasi
Gillian
G
Murphy
William R
WR
English
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D016392:Proto-Oncogene Proteins pp60(c-src); D053511:Matrix Metalloproteinase 14