HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 50, 36283-36291, December 14, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/50/36283    most recent M706290200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Golubkov, V. S. Articles by Strongin, A. Y. Search for Related Content PubMed PubMed Citation Articles by Golubkov, V. S. Articles by Strongin, A. Y. Social Bookmarking                      What's this?

Proteolysis of the Membrane Type-1 Matrix Metalloproteinase Prodomain

IMPLICATIONS FOR A TWO-STEP PROTEOLYTIC PROCESSING AND ACTIVATION^*

From the Burnham Institute for Medical Research, La Jolla, California 92037

Membrane type-1 matrix metalloproteinase (MT1-MMP) exerts its enhanced activity in multiple cancer types. Understanding the activation process of MT1-MMP is essential for designing novel and effective cancer therapies. Like all of the other MMPs, MT1-MMP is synthesized as a zymogen, the latency of which is maintained by its inhibitory prodomain. Proteolytic processing of the prodomain transforms the zymogen into a catalytically active enzyme. A sequential, two-step activation process is normally required for MMPs. Our in silico modeling suggests that the prodomain of MT1-MMP exhibits a conserved three helix-bundled structure and a "bait" loop region linking helixes 1 and 2. We hypothesized and then confirmed that in addition to furin cleavage there is also a cleavage at the bait region in the activation process of MT1-MMP. A two-step sequential activation of MT1-MMP is likely to include the MMP-dependent cleavage at either P⁴⁷GDL⁵⁰ or P⁵⁸QSL⁶¹ or at both sites of the bait region. This event results in the activation intermediate. The activation process is then completed by a proprotein convertase cleaving the inhibitory prodomain at the R¹⁰⁸RKR¹¹¹Y¹¹² site, where Tyr¹¹² is the N-terminal residue of the mature MT1-MMP enzyme. Our findings suggest that the most efficient activation results from a two-step mechanism that eventually is required for the degradation of the inhibitory prodomain and the release of the activated, mature MT1-MMP enzyme. These findings shed more light on the functional role of the inhibitory prodomain and on the proteolytic control of MT1-MMP activation, a crucial process that may be differentially regulated in normal and cancer cells.

Received for publication, July 31, 2007 , and in revised form, September 26, 2007.

^* The work was supported by National Institutes of Health Grants CA83017 and CA77470, Susan G. Komen Breast Cancer Foundation Grant BCTR0601231 (to A. Y. S.), and National Institutes of Health Grant RR020843 (to A. Y. S. and J. W. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 10901 North Torrey Pines Rd., La Jolla, CA. Tel.: 858-713-6271; E-mail: strongin{at}burnham.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. G. Remacle, S. A. Shiryaev, E.-S. Oh, P. Cieplak, A. Srinivasan, G. Wei, R. C. Liddington, B. I. Ratnikov, A. Parent, R. Desjardins, et al. Substrate Cleavage Analysis of Furin and Related Proprotein Convertases: A COMPARATIVE STUDY J. Biol. Chem., July 25, 2008; 283(30): 20897 - 20906. [Abstract] [Full Text] [PDF]