TY - JOUR
T1 - Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase
AU - Golubkov, Vladislav S.
AU - Cieplak, Piotr
AU - Chekanov, Alexei V.
AU - Ratnikov, Boris I.
AU - Aleshin, Alexander E.
AU - Golubkova, Natalya V.
AU - Postnova, Tatiana I.
AU - Radichev, Ilian A.
AU - Rozanov, Dmitri V.
AU - Zhu, Wenhong
AU - Motamedchaboki, Khatereh
AU - Strongin, Alex Y.
PY - 2010/9/3
Y1 - 2010/9/3
N2 - 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.
AB - 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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U2 - 10.1074/jbc.M110.135442
DO - 10.1074/jbc.M110.135442
M3 - Article
C2 - 20605791
AN - SCOPUS:77956241148
SN - 0021-9258
VL - 285
SP - 27726
EP - 27736
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 36
ER -