Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively.
The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH(2)- and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH(2)-terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.
Liu
Y-J
YJ
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Xu
Y
Y
Yu
Q
Q
D051722:ADAM Proteins / Q000235:genetics / Q000494:pharmacology*; D000071097:ADAMTS1 Protein; D000595:Amino Acid Sequence; D066258:Amphiregulin; D000818:Animals; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D049109:Cell Proliferation; D003094:Collagen; D004338:Drug Combinations; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007797:Laminin; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D011509:Proteoglycans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; D066258:Amphiregulin; D003094:Collagen; D004338:Drug Combinations; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007797:Laminin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011509:Proteoglycans; D018719:Erb-b2 Receptor Tyrosine Kinases; C587848:AREG protein, human; C587849:Areg protein, mouse; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C059485:matrigel; C103859:ADAMTS1 protein, human