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PMID:20159608

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Citation

Redondo-Muñoz, J, Ugarte-Berzal, E, Terol, MJ, Van den Steen, PE, Hernández del Cerro, M, Roderfeld, M, Roeb, E, Opdenakker, G, García-Marco, JA and García-Pardo, A (2010) Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain. Cancer Cell 17:160-72

Abstract

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 alpha4beta1 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.

Links

PubMed Online version:10.1016/j.ccr.2009.12.044

Keywords

Apoptosis; B-Lymphocytes/metabolism; B-Lymphocytes/pathology; Cell Adhesion; Cells, Cultured; Gene Expression Regulation, Leukemic; Humans; Integrin alpha4beta1/metabolism; Leukemia, Lymphocytic, Chronic, B-Cell/genetics; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism; Leukemia, Lymphocytic, Chronic, B-Cell/pathology; Matrix Metalloproteinase 9/chemistry; Matrix Metalloproteinase 9/metabolism; Matrix Metalloproteinase 9/physiology; Mitochondria/metabolism; Mitochondria/ultrastructure; Phosphorylation; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; STAT3 Transcription Factor/metabolism; Signal Transduction; src-Family Kinases/metabolism; src-Family Kinases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ITB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07948

F

Seeded From UniProt

complete

HUMAN:ITB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P13612

F

Seeded From UniProt

complete

HUMAN:LYN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05556

F

Seeded From UniProt

complete

HUMAN:ITA4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05556

F

Seeded From UniProt

complete


See also

References

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