Calreticulin is directly involved in anti-alpha 3 integrin antibody-mediated secretion and activation of matrix metalloprotease-2

Matrix metalloprotease-2 (MMP-2) plays a pivotal role in cancer invasion an d metastasis. Invasive human rhabdomyosarcoma cells (RD) secrete proMMP-2. We recently reported that anti-alpha3 integrin antibody induced the activat ed form of MMP-2 and enhanced proMMP-2 secretion by RD cells with concomita nt enhancement of RD cell invasion. Since recent studies showed that calret iculin interacts with integrin a subunit, we hypothesized that calreticulin may be involved in signal transduction of anti-alpha3 integrin antibody-me diated MMP-2 secretion and activation. Here we demonstrate that anti-alpha3 integrin antibody induced a transient enhanced interaction of calreticulin with alpha3 integrin. Transfection of antisense oligonucleotides of calret iculin in RD cells abrogated the interaction between calreticulin and alpha 3 integrin, and completely suppressed activation of MMP-2 and enhanced secr etion of proMMP-2 induced by anti-alpha3 integrin antibody. Transient overe xpression of calreticulin cDNA in RD cells significantly increased secretio n of proMMP-2. The results demonstrate for the first time that calreticulin is directly involved in MMP-2 secretion and activation. (C) 2001 academic Press.