University of Cambridge, Department of Oncology, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
J Cell Sci. 2010 Dec 1;123(Pt 23):4182-93. doi: 10.1242/jcs.062711. Epub 2010 Nov 9.
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.
膜型基质金属蛋白酶 1（MT1-MMP）是一种锌依赖性的 I 型跨膜金属蛋白酶，参与细胞外基质的蛋白水解、迁移和侵袭，其水平升高与癌症预后不良相关。MT1-MMP 介导的癌细胞中基因的转录调控可能有助于肿瘤生长，尽管这在机制水平上还了解甚少。在这项研究中，我们研究了 MT1-MMP 调节乳腺癌细胞中 VEGF-A 表达的机制。我们发现，MT1-MMP 调节 VEGFR-2 的细胞表面定位，并与 VEGFR-2 和 Src 形成复合物，该复合物依赖于 MT1-MMP 的血红素结合域，且不依赖其催化活性。尽管 VEGFR-2 的定位不依赖于 MT1-MMP 的催化和细胞内结构域，但依赖于 VEGFR-2 活性的细胞内信号转导导致 VEGF-A 转录仍需要 MT1-MMP 的催化和细胞内结构域，包括 Y573、C574 和 DKV582 残基。然而，MT1-MMP 的催化活性的功能存在冗余性，因为在表达无活性 MT1-MMP 的细胞中，MMP-2 或 MMP-7 可以替代其功能。依赖于 MT1-MMP-VEGFR-2-Src 复合物的信号级联激活 Akt 和 mTOR，最终导致 VEGF-A 转录增加。
