Reference : TIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in ...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/34890
TIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells
English
Sounni, Nor Eddine mailto [Université de Liège - ULg > Département des sciences cliniques > Labo de biologie des tumeurs et du développement >]
Rozanov, D. V. [ > > ]
Remacle, A. G. [ > > ]
Golubkov, V. S. [ > > ]
Noël, Agnès mailto [Université de Liège - ULg > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme >]
Strongin, A. Y. [ > > ]
2010
International Journal of Cancer = Journal International du Cancer
Wiley Liss, Inc.
126
5
1067-78
Yes (verified by ORBi)
International
0020-7136
1097-0215
New York
NY
[en] MT1-MMP ; TIMP-2 ; cell migration ; ERK ; MEK
[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.
http://hdl.handle.net/2268/34890
10.1002/ijc.24690

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