Journal
CANCER CELL
Volume 17, Issue 2, Pages 160-172Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2009.12.044
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Funding
- Ministerio de Ciencia e Innovacion [PI060400, SAF2009-07035, RTICC RD06/0020/0011, PI061637, RTICC RD06/0020/0080]
- Fundacion de Investigacion Medica Mutua Madrilena
- Geconcerteerde OnderzoeksActies
- Fund for Scientific Research-Flanders (FWO-Vlaanderen)
- Deutsche Forschungsgemeinschaft [Ro 957/6-1, Ro 957/7-1]
- Fundacion Ramon Areces
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Matrix metalloproteinase-9 (MMP-9) is the major MMP produced by B-CLL cells and contributes to their tissue infiltration by degrading extracellular and membrane-anchored substrates. Here we describe a different function for MMP-9 in B-CLL, which involves the hemopexin domain rather than its catalytic function. Binding of soluble or immobilized (pro)MMP-9, a catalytically inactive proMMP-9 mutant, or the MMP-9 hemopexin domain to its docking receptors alpha 4 beta 1 integrin and CD44v, induces an intracellular signaling pathway that prevents B-CLL apoptosis. This pathway is induced in all B-CLL cases, is active in B-CLL lymphoid tissues, and consists of Lyn activation, STAT3 phosphorylation, and Mcl-1 upregulation. Our results establish that MMP/receptor binding induces intracellular survival signals and highlight the role of (pro)MMP-9 in B-CLL pathogenesis.
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