Internal Cleavages of the Autoinhibitory Prodomain Are Required for Membrane Type 1 Matrix Metalloproteinase Activation,although Furin Cleavage Alone Generates Inactive Proteinase |
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Authors: | Vladislav S Golubkov Piotr Cieplak Alexei V Chekanov Boris I Ratnikov Alexander E Aleshin Natalya V Golubkova Tatiana I Postnova Ilian A Radichev Dmitri V Rozanov Wenhong Zhu Khatereh Motamedchaboki Alex Y Strongin |
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Institution: | From the Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037 |
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Abstract: | The functional activity of invasion-promoting membrane type 1 matrix metalloproteinase (MT1-MMP) is elevated in cancer. This elevated activity promotes cancer cell migration, invasion, and metastasis. MT1-MMP is synthesized as a zymogen, the latency of which is maintained by its prodomain. Excision by furin was considered sufficient for the prodomain release and MT1-MMP activation. We determined, however, that the full-length intact prodomain released by furin alone is a potent autoinhibitor of MT1-MMP. Additional MMP cleavages within the prodomain sequence are required to release the MT1-MMP enzyme activity. Using mutagenesis of the prodomain sequence and mass spectrometry analysis of the prodomain fragments, we demonstrated that the intradomain cleavage of the PGD↓L50 site initiates the MT1-MMP activation, whereas the 108RRKR111↓Y112 cleavage by furin completes the removal and the degradation of the autoinhibitory prodomain and the liberation of the functional activity of the emerging enzyme of MT1-MMP. |
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Keywords: | Breast Cancer Matrix Metalloproteinase Protein Degradation Protein Folding Protein Secretion Serine Protease MT1-MMP Furin Prodomain Proteolysis |
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