Cancer Cell Biology

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Timp-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells

  1. Nor Eddine Sounni1,
  2. Dmitri V. Rozanov1,
  3. Albert G. Remacle1,
  4. Vladislav S. Golubkov1,
  5. Agnes Noel2,
  6. Alex Y. Strongin1,†,*

Article first published online: 23 JUN 2009

DOI: 10.1002/ijc.24690

Issue

International Journal of Cancer

International Journal of Cancer

Volume 126, Issue 5, pages 1067–1078, 1 March 2010

Additional Information

How to Cite

Sounni, N. E., Rozanov, D. V., Remacle, A. G., Golubkov, V. S., Noel, A. and Strongin, A. Y. (2010), Timp-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells. Int. J. Cancer, 126: 1067–1078. doi: 10.1002/ijc.24690

Author Information

  1. 1

    Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA

  2. 2

    Laboratory of Biology of Tumors and Development, University of Liege, Liege, Belgium

  1. †

    Fax: +858-795-5225

*Burnham Institute for Medical Research, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA. Tel: +858-795-5225

Publication History

  1. Issue published online: 27 DEC 2009
  2. Article first published online: 23 JUN 2009
  3. Accepted manuscript online: 23 JUN 2009 12:00AM EST
  4. Manuscript Accepted: 16 JUN 2009
  5. Manuscript Received: 31 MAR 2009

Funded by

  • NIH. Grant Numbers: CA83017, CA77470, RR020843
  • Susan G. Komen Breast Cancer Foundation. Grant Number: BCTR123106
  • European Framework Program FP7 microenvimet

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Keywords:

  • MT1-MMP;
  • TIMP-2;
  • cell migration;
  • ERK;
  • MEK

Abstract

Both invasion-promoting MT1-MMP and its physiological inhibitorTIMP-2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in vitro, clinical data suggest that TIMP-2 expression is positively associated with tumor recurrence, thus emphasizing the wide-ranging role of TIMP-2 in malignancies. To shed light on this role of TIMP-2, we report that low concentrations of TIMP-2, by interacting with MT1-MMP (a specific membrane receptor of TIMP-2), induce the MEK/ERK signaling cascade in fibrosarcoma HT1080 cells which express MT1-MMP naturally. TIMP-2 binding with cell surface-associated MT1-MMP stimulates phosphorylation of MEK1/2, which is upstream of ERK1/2, and the ERK1/2 substrate p90RSK. Consistent with volumes of literature, we confirmed that the activation of ERK stimulated cell migration. Both the transcriptional silencing of MT1-MMP and the inhibition of MEK1/2 reversed the signaling effects of TIMP-2/MT1-MMP while the active site-targeting MMP inhibitor GM6001 did not. Our data suggest that both the interactions of TIMP-2 with MT1-MMP, which activate the pro-migratory ERK signaling cascade,and the conventional inhibition of MT1-MMP's catalytic activity by TIMP-2, play a role in the invasion-promoting function of MT1-MMP. The TIMP-2-induced stimulation of ERK signaling in cancer cells explains the direct, as opposed to the inverse, association of TIMP-2 expression with poor prognosis in cancer.

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