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Blood, 1 July 2008, Vol. 112, No. 1, pp. 169-178.
Prepublished online as a Blood First Edition Paper on March 7, 2008; DOI 10.1182/blood-2007-08-109249.
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NEOPLASIA
 4β1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells
Javier Redondo-Muñoz1,
Estefanía Ugarte-Berzal1,
José A. García-Marco2,
Mercedes Hernández del Cerro1,
Philippe E. Van den Steen3,
Ghislain Opdenakker3,
María José Terol4, and
Angeles García-Pardo1
1 Departamento de Fisiopatología Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain;
2 Servicio de Hematología, Hospital Puerta de Hierro, Madrid, Spain;
3 Rega Institute for Medical Research, University of Leuven, Leuven, Belgium; and
4 Servicio de Hematología y Medicina Oncológica, Hospital Clínico, Valencia, Spain
As B-cell chronic lymphocytic leukemia (B-CLL) progresses, malignant cells extravasate and infiltrate lymphoid tissues. Several molecules, including gelatinase B/MMP-9, contribute to these processes. Although mainly a secreted protease, some MMP-9 is present at the B-CLL cell surface and the function, mode of anchoring, and interactions of this MMP-9 are unknown. Here we show that anti–MMP-9 antibodies immunoprecipitated a 190-kDa CD44v isoform and  4β1 integrin from B-CLL cells, but not from normal B cells. Function-blocking antibodies to 4β1 or CD44, or transfection with specific siRNAs, decreased cell-associated proMMP-9 and increased the secreted form. B-CLL cells attached to and bound proMMP-9 and active MMP-9, and this was inhibited by blocking the expression or function of 4β1 or CD44. The MMP-9 hemopexin domain was critical in these interactions. 4β1 and 190-kDa CD44v (but not CD44H) formed a complex at the cell surface, since they both coimmunoprecipitated with anti-4, anti-β1, or anti-CD44 antibodies. Immunofluorescence analyses confirmed that 4β1 and CD44v colocalized with MMP-9. Binding of proMMP-9 inhibited B-CLL cell migration, and this required MMP-9 proteolytic activity. Thus, we have identified 4β1 and CD44v as a novel proMMP-9 cell surface docking complex and show that cell-associated MMP-9 may regulate B-CLL cell migration and arrest.
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