Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion.
Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(-) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL.
Lagarrigue
Frédéric
F
Département Oncogénèse, Université Toulouse III Paul-Sabatier, Toulouse, France.
Dupuis-Coronas
Sophie
S
Ramel
Damien
D
Delsol
Georges
G
Tronchère
Hélène
H
Payrastre
Bernard
B
Gaits-Iacovoni
Frédérique
F
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
C497483:CD44 protein, human; D004151:Dipeptides; D004792:Enzyme Precursors; D018841:HSP90 Heat-Shock Proteins; D018960:Hyaluronan Receptors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C107953:RAC1 protein, human; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein