Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation onthe cell surface and promotes tumor cell invasion

Itoh, Y Takamura, A Ito, N Maru, Y Sato, H Suenaga, N Aoki, T Seiki, M

Y. Itoh et al., Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation onthe cell surface and promotes tumor cell invasion, EMBO J, 20(17), 2001, pp. 4782-4793

54

INGLESE

Article

Molecular Biology & Genetics

EMBO JOURNAL

0261-4189 → ACNP

20

17

2001

4782 - 4793

ISI

0261-4189(20010903)20:17<4782:HCFOMF>2.0.ZU;2-E

Activation of proMMP-2 by MT1-MMP is considered to be a critical event in c ancer cell invasion. In the activation step, TIMP-2 bound to MT1-MMP on the cell surface acts as a receptor for proMMP-2. Subsequently, adjacent TIMP- 2-free MT1-MMP activates the proMMP-2 in the ternary complex. In this study , we demonstrate that MT1-MMP forms a homophilic complex through the hemope xin-like (PEX) domain that acts as a mechanism to keep MT1-MMP molecules cl ose together to facilitate proMMP-2 activation. Deletion of the PEX domain in MT1-MMP, or swapping the domain with the one derived from MT4-MMP, aboli shed the ability to activate proMMP-2 on the cell surface without affecting the proteolytic activities. In addition, expression of the mutant MT1-MMP lacking the catalytic domain (MT1PEX-F) efficiently inhibited complex forma tion of the full-length enzymes and activation of proMMP-2. Furthermore, ex pression of MT1PEX-F inhibited proMMP-2 activation and Matrigel invasion ac tivity of invasive human fibrosarcoma HT1080 cells. These findings elucidat e a new function of the PEX domain: regulating MT1-MMP activity on the cell surface, which accelerates cellular invasiveness in the tissue.