title: Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase.
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/L(50) site initiates the MT1-MMP activation, whereas the (108)RRKR(111)/Y(112) 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.
authors.affiliation: Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Golubkov
authors.forename: Piotr
authors.initials: P
authors.lastname: Cieplak
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Chekanov
authors.forename: Boris I
authors.initials: BI
authors.lastname: Ratnikov
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Aleshin
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Golubkova
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Postnova
authors.forename: Ilian A
authors.initials: IA
authors.lastname: Radichev
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Rozanov
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhu
authors.forename: Khatereh
authors.initials: K
authors.lastname: Motamedchaboki
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Strongin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045683:Furin / Q000378:metabolism*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017434:Protein Structure, Tertiary
chemical_list: D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D045683:Furin; D053511:Matrix Metalloproteinase 14