Non-canonical activation of Notch1 by Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) controls melanoma cell proliferation [Signal Transduction]

February 3rd, 2014 by Ma, J., Tang, X., Wong, P., Jacobs, B., Borden, E. C., Bedogni, B.

Notch1 is an evolutionarily conserved signaling molecule required for stem cell maintenance that is inappropriately reactivated in several cancers. We have previously shown that melanomas reactivate Notch1 and require its function for growth and survival. However, no Notch1 activating mutations have been observed in melanoma, suggesting the involvement of other activating mechanisms. Notch1 activation requires two cleavage steps: first by a protease, then by g-secretase, which releases the active intracellular domain (Notch1NIC). Interestingly, although ADAM10 and 17 are generally accepted as the proteases responsible of Notch1 cleavage, here we show that MT1-MMP, a membrane-tethered matrix metalloproteinase involved in the pathogenesis of a number of tumors, is a novel protease required for the cleavage of Notch1 in melanoma cells. We find that active Notch1 and MT1-MMP expression correlate significantly in over 70% of melanoma tumors and 80% of melanoma cell lines, while such correlation does not exist between Notch1NIC and ADAM10 or 17. Modulation of MT1-MMP expression in melanoma cells affects Notch1 cleavage, while MT1-MMP expression in ADAM10/17 double knock out fibroblasts restores the processing of Notch1, indicating MT1-MMP is sufficient to promote Notch1 activation independently of the canonical proteases. Importantly, we find that MT1-MMP interacts with Notch1 at the cell membrane, supporting a potential direct cleavage mechanism of MT1-MMP on Notch1; and MT1-MMP dependent activation of Notch1 sustains melanoma cell growth. Together, the data highlight a novel mechanism of activation of Notch1 in melanoma cells and identify Notch1 as a new MT1-MMP substrate that plays important biological roles in melanoma.
  • Posted in Journal of Biological Chemistry, Publications
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