Internal cleavages of the autoinhibitory prodomain are required for membrane type 1 matrix metalloproteinase activation, although furin cleavage alone generates inactive proteinase.
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.
Golubkov
Vladislav S
VS
Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Cieplak
Piotr
P
Chekanov
Alexei V
AV
Ratnikov
Boris I
BI
Aleshin
Alexander E
AE
Golubkova
Natalya V
NV
Postnova
Tatiana I
TI
Radichev
Ilian A
IA
Rozanov
Dmitri V
DV
Zhu
Wenhong
W
Motamedchaboki
Khatereh
K
Strongin
Alex Y
AY
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
D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D045683:Furin; D053511:Matrix Metalloproteinase 14