基质金属蛋白酶-9 通过其血红素结合蛋白结构域促进慢性淋巴细胞白血病 B 细胞存活。

Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain.

机构信息

Centro de Investigaciones Biológicas, Madrid, Spain.

出版信息

Cancer Cell. 2010 Feb 17;17(2):160-72. doi: 10.1016/j.ccr.2009.12.044.

DOI:10.1016/j.ccr.2009.12.044

PMID:20159608

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.

摘要

基质金属蛋白酶-9（MMP-9）是 B-CLL 细胞产生的主要 MMP，通过降解细胞外基质和膜锚定底物促进其组织浸润。在这里，我们描述了 MMP-9 在 B-CLL 中的另一种功能，涉及血影蛋白结构域而不是其催化功能。可溶性或固定化（原）MMP-9、催化失活的原 MMP-9 突变体或 MMP-9 血影蛋白结构域与其对接受体α4β1 整合素和 CD44v 的结合，诱导一种阻止 B-CLL 细胞凋亡的细胞内信号通路。该通路在所有 B-CLL 病例中均被诱导，在 B-CLL 淋巴组织中具有活性，并且包括 Lyn 激活、STAT3 磷酸化和 Mcl-1 的上调。我们的结果确立了 MMP/受体结合诱导细胞内存活信号，并强调了（原）MMP-9 在 B-CLL 发病机制中的作用。