Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain.
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.
Centro de Investigaciones Biológicas, Madrid, Spain.
Javier
J
Redondo-Muñoz
Estefanía
E
Ugarte-Berzal
María José
MJ
Terol
Philippe E
PE
Van den Steen
Mercedes
M
Hernández del Cerro
Martin
M
Roderfeld
Elke
E
Roeb
Ghislain
G
Opdenakker
José A
JA
García-Marco
Angeles
A
García-Pardo
D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology
D039041:Integrin alpha4beta1; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020780:Matrix Metalloproteinase 9