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A 17-residue sequence from the matrix metalloproteinase-9 (MMP-9) hemopexin domain binds α4β1 integrin and inhibits MMP-9-induced functions in chronic lymphocytic leukemia B cells

AuthorsUgarte-Berzal, Estefanía ; Bailón, Elvira ; Amigo-Jiménez, Irene ; Vituri, Cidonia L.; Hernández del Cerro, Mercedes ; Terol, María José; Albar, Juan Pablo; Rivas, Germán ; García-Marco, José A.; García-Pardo, Angeles
Cell Death
Cell Invasion
Cell Signaling
Hemopexin domain
Matrix metalloproteinase 9
Issue Date10-Aug-2012
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 287(33): 27601-27613(2012)
AbstractWe previously showed that pro-matrix metalloproteinase-9 (proMMP-9) binds to B chronic lymphocytic leukemia (B-CLL) cells and contributes to B-CLL progression by regulating cell migration and survival. Induction of cell survival involves a non-proteolytic mechanism and the proMMP-9 hemopexin domain (PEX9). To help design specific inhibitors of proMMP-9-cell binding, we have now characterized B-CLL cell interaction with the isolated PEX9. B-CLL cells bound soluble and immobilized GST-PEX9, but not GST, and binding was mediated by α4β1 integrin. The ability to recognize PEX9 was observed in all 20 primary samples studied irrespective of their clinical stage or prognostic marker phenotype. By preparing truncated forms of GST-PEX9 containing structural blades B1B2 or B3B4, we have identified B3B4 as the primary α4β1 integrin-interacting region within PEX9. Overlapping synthetic peptides spanning B3B4 were then tested in functional assays. Peptide P3 (FPGVPLDTHDVFQYREKAYFC), a sequence present in B4 or smaller versions of this sequence (peptides P3a/P3b), inhibited B-CLL cell adhesion to GST-PEX9 or proMMP-9, with IC50 values of 138 and 279 μm, respectively. Mutating the two aspartate residues to alanine rendered the peptides inactive. An anti-P3 antibody also inhibited adhesion to GST-PEX9 and proMMP-9. GST-PEX9, GST-B3B4, and P3/P3a/P3b peptides inhibited B-CLL cell transendothelial migration, whereas the mutated peptide did not. B-CLL cell incubation with GST-PEX9 induced intracellular survival signals, namely Lyn phosphorylation and Mcl-1 up-regulation, and this was also prevented by the P3 peptides. The P3 sequence may, therefore, constitute an excellent target to prevent proMMP-9 contribution to B-CLL pathogenesis
Description13 páginas, 7 figuras, 2 tablas -- PAGS nros. 27601-27613
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M112.354670
Appears in Collections:(CIB) Artículos
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