Article (Scientific journals)
TIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells
Sounni, Nor Eddine; Rozanov, D. V.; Remacle, A. G. et al.
2010In International Journal of Cancer, 126 (5), p. 1067-78
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Keywords :
MT1-MMP; TIMP-2; cell migration; ERK; MEK
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sounni, Nor Eddine  ;  Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Rozanov, D. V.
Remacle, A. G.
Golubkov, V. S.
Noël, Agnès ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Strongin, A. Y.
Language :
English
Title :
TIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells
Publication date :
2010
Journal title :
International Journal of Cancer
ISSN :
0020-7136
eISSN :
1097-0215
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
126
Issue :
5
Pages :
1067-78
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 07 January 2010

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