Calreticulin is directly involved in anti-alpha3 integrin antibody-mediated secretion and activation of matrix metalloprotease-2.
Matrix metalloprotease-2 (MMP-2) plays a pivotal role in cancer invasion and metastasis. Invasive human rhabdomyosarcoma cells (RD) secrete proMMP-2. We recently reported that anti-alpha3 integrin antibody induced the activated form of MMP-2 and enhanced proMMP-2 secretion by RD cells with concomitant enhancement of RD cell invasion. Since recent studies showed that calreticulin interacts with integrin alpha subunit, we hypothesized that calreticulin may be involved in signal transduction of anti-alpha3 integrin antibody-mediated 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 calreticulin in RD cells abrogated the interaction between calreticulin and alpha3 integrin, and completely suppressed activation of MMP-2 and enhanced secretion of proMMP-2 induced by anti-alpha3 integrin antibody. Transient overexpression of calreticulin cDNA in RD cells significantly increased secretion of proMMP-2. The results demonstrate for the first time that calreticulin is directly involved in MMP-2 secretion and activation.
Ito
H
H
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Japan.
Seyama
Y
Y
Kubota
S
S
D000906:Antibodies / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D037282:Calreticulin; D004789:Enzyme Activation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D039422:Integrin alpha3; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D012208:Rhabdomyosarcoma / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D012261:Ribonucleoproteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D037282:Calreticulin; D039422:Integrin alpha3; D016023:Integrins; D016376:Oligonucleotides, Antisense; D012261:Ribonucleoproteins; D020778:Matrix Metalloproteinase 2