Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

Oncogene volume 25, pages 2452–2467 (2006)Cite this article

Abstract

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 NH2- and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH2-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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 3
Figure 2
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

ADAMTS-1:

a disintegrin and metalloproteinase with thrombospondin motifs-1

ADAMTS-1E/Q:

a protease-dead ADAMTS-1 mutant

ADAMTS-1NTF:

the NH2-terminal ADAMTS-1 fragment

ADAMTS-1CTF:

the COOH-terminal ADAMTS-1 fragment

ADAMTSNTCF:

the NH2-terminal cleavage fragment of ADAMTS-1

ADAMTSCTCF:

the COOH-terminal cleavage of ADAMTS-1

APMA:

p-aminophenylmercuric acetate

AR:

amphiregulin

bFGF:

basic fibroblast growth factor

BrdU:

5-bromo-2′-deoxy-uridine

CMFDA:

Green 5-chloromethyl-fluorescein diacetate

Cys-rich:

cysteine-rich

DMEM:

Dulbecco's modified Eagle's medium

ECM:

extracellular matrix

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

FBS:

fetal bovine serum

GAG:

glycosaminoglycans

GF:

growth factors

HS:

heparan sulfate

HSPGs:

heparan sulfate proteoglycans

HB-EGF:

heparin-binding epidermal growth factor

H&E:

hematoxylin and eosin

HUVECs:

human umbilical vein endothelial cells

kDa:

kilodalton

LLC:

Lewis lung carcinoma

MMP:

matrix metalloproteinase

RT–PCR:

reverse transcriptase–polymerase chain reaction

PKC:

protein kinase C

TA3:

TA3 murine mammary carcinoma

TPA:

12-O-tetradecanoyl-phorbol-13-acetate

TSP-1:

thrombospondin type I-like

Tsp-1:

thrombospondin-1

Tsp-2:

thrombospondin-2

VEGF:

vascular endothelial growth factor

vWF:

von Willebrand factor

References

  • Adams JC . (2001). Annu Rev Cell Dev Biol 17: 25–51.

  • Billings SD, Southall MD, Li T, Cook PW, Baldridge L, Moores WB et al. (2003). Am J Pathol 163: 2451–2458.

  • Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF et al. (1997). Nature 385: 729–733.

  • Blobel CP . (2000). Curr Opin Cell Biol 12: 606–612.

  • Bostwick DG, Qian J, Maihle NJ . (2004). Prostate 58: 164–168.

  • Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett PT, Leahy DJ et al. (2003). Mol Cell 12: 541–552.

  • Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V, Lopez-Otin C . (2002). Gene 283: 49–62.

  • Colige A, Ruggiero F, Vandenberghe I, Dubail J, Kesteloot F, Van Beeumen J et al. (2005). J Biol Chem 280: 34397–34408.

  • Cook PW, Pittelkow MR, Keeble WW, Graves-Deal R, Coffey Jr RJ, Shipley GD . (1992). Cancer Res 52: 3224–3227.

  • Ebert M, Yokoyama M, Kobrin MS, Friess H, Lopez ME, Buchler MW et al. (1994). Cancer Res 54: 3959–3962.

  • Flannery CR, Zeng W, Corcoran C, Collins-Racie LA, Chockalingam PS, Hebert T et al. (2002). J Biol Chem 277: 42775–42780.

  • Gschwind A, Hart S, Fischer OM, Ullrich A . (2003). EMBO J 22: 2411–2421.

  • Hamid AS, O'Donnell AL, Balu D, Pohl MB, Seyler MJ, Mohamed S et al. (2000). Cancer Res 60: 7094–7098.

  • Harris RC, Chung E, Coffey RJ . (2003). Exp Cell Res 284: 2–13.

  • Herren B . (2002). News Physiol Sci 17: 73–76.

  • Iruela-Arispe ML, Carpizo D, Luque A . (2003). Ann NY Acad Sci 995: 183–190.

  • Iruela-Arispe ML, Lombardo M, Krutzsch HC, Lawler J, Roberts DD . (1999). Circulation 100: 1423–1431.

  • Iwamoto R, Yamazaki S, Asakura M, Takashima S, Hasuwa H, Miyado K et al. (2003). Proc Natl Acad Sci USA 100: 3221–3226.

  • Jackson LF, Qiu TH, Sunnarborg SW, Chang A, Zhang C, Patterson C et al. (2003). EMBO J 22: 2704–2716.

  • Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, Cordon-Cardo C et al. (2003). Cancer Cell 3: 537–549.

  • Kitadai Y, Yasui W, Yokozaki H, Kuniyasu H, Ayhan A, Haruma K et al. (1993). Jpn J Cancer Res 84: 879–884.

  • Kuno K, Bannai K, Hakozaki M, Matsushima K, Hirose K . (2004). Biochem Biophys Res Commun 319: 1327–1333.

  • Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K . (1997). J Biol Chem 272: 556–562.

  • Kuno K, Matsushima K . (1998). J Biol Chem 273: 13912–13917.

  • Kuno K, Okada Y, Kawashima H, Nakamura H, Miyasaka M, Ohno H et al. (2000). FEBS Lett 478: 241–245.

  • Kuno K, Terashima Y, Matsushima K . (1999). J Biol Chem 274: 18821–18826.

  • Lee DC, Sunnarborg SW, Hinkle CL, Myers TJ, Stevenson MY, Russell WE et al. (2003). Ann NY Acad Sci 995: 22–38.

  • LeJeune S, Leek R, Horak E, Plowman G, Greenall M, Harris AL . (1993). Cancer Res 53: 3597–3602.

  • Luque A, Carpizo DR, Iruela-Arispe ML . (2003). J Biol Chem 278: 23656–23665.

  • Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR et al. (2002). Science 295: 140–143.

  • Massagué J, Pandiella A . (1993). Annu Rev Biochem 62: 515–541.

  • Masui T, Hosotani R, Tsuji S, Miyamoto Y, Yasuda S, Ida J et al. (2001). Clin Cancer Res 7: 3437–3443.

  • Merlos-Suarez A, Ruiz-Paz S, Baselga J, Arribas J . (2001). J Biol Chem 276: 48510–48517.

  • Miao WM, Seng WL, Duquette M, Lawler P, Laus C, Lawler J . (2001). Cancer Res 61: 7830–7839.

  • Minn AJ, Kang Y, Serganova I, Gupta GP, Giri DD, Doubrovin M et al. (2005). J Clin Invest 115: 44–55.

  • Miyamoto S, Hirata M, Yamazaki A, Kageyama T, Hasuwa H, Mizushima H et al. (2004). Cancer Res 64: 5720–5727.

  • Nokihara H, Yanagawa H, Nishioka Y, Yano S, Mukaida N, Matsushima K et al. (2000). Cancer Res 60: 7002–7007.

  • Normanno N, Kim N, Wen D, Smith K, Harris AL, Plowman G et al. (1995). Breast Cancer Res Treat 35: 293–297.

  • O'Reilly MS, Pirie-Shepherd S, Lane WS, Folkman J . (1999). Science 285: 1926–1928.

  • Panico L, D'Antonio A, Salvatore G, Mezza E, Tortora G, De Laurentiis M et al. (1996). Int J Cancer 65: 51–56.

  • Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC et al. (1998). Science 282: 1281–1284.

  • Pfeifer A, Kessler T, Silletti S, Cheresh DA, Verma IM . (2000). Proc Natl Acad Sci USA 97: 12227–12232.

  • Porter S, Clark IM, Kevorkian L, Edwards DR . (2005). Biochem J 386: 15–27.

  • Porter S, Scott SD, Sassoon EM, Williams MR, Jones JL, Girling AC et al. (2004). Clin Cancer Res 10: 2429–2440.

  • Rodriguez-Manzaneque JC, Milchanowski AB, Dufour EK, Leduc R, Iruela-Arispe ML . (2000). J Biol Chem 275: 33471–33479.

  • Russell DL, Doyle KM, Ochsner SA, Sandy JD, Richards JS . (2003). J Biol Chem 278: 42330–42339.

  • Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J et al. (2004). J Cell Biol 164: 769–779.

  • Salomon DS, Normanno N, Ciardiello F, Brandt R, Shoyab M, Todaro GJ . (1995). Breast Cancer Res Treat 33: 103–114.

  • Sandy JD, Westling J, Kenagy RD, Iruela-Arispe ML, Verscharen C, Rodriguez-Mazaneque JC et al. (2001). J Biol Chem 276: 13372–13378.

  • Shindo T, Kurihara H, Kuno K, Yokoyama H, Wada T, Kurihara Y et al. (2000). J Clin Invest 105: 1345–1352.

  • Stern DF . (2000). Breast Cancer Res 2: 176–183.

  • Sternlicht MD, Werb Z . (2001). Annu Rev Cell Dev Biol 17: 463–516.

  • Streit M, Velasco P, Riccardi L, Spencer L, Brown LF, Janes L et al. (2000). EMBO J 19: 3272–3282.

  • Sunnarborg SW, Hinkle CL, Stevenson M, Russell WE, Raska CS, Peschon JJ et al. (2002). J Biol Chem 277: 12838–12845.

  • Tolsma SS, Volpert OV, Good DJ, Frazier WA, Polverini PJ, Bouck N . (1993). J Cell Biol 122: 497–511.

  • Tucker RP . (2004). Int J Biochem Cell Biol 36: 969–974.

  • Vazquez F, Hastings G, Ortega MA, Lane TF, Oikemus S, Lombardo M et al. (1999). J Biol Chem 274: 23349–23357.

  • Visscher DW, Sarkar FH, Kasunic TC, Reddy KB . (1997). Breast Cancer Res Treat 45: 75–80.

  • Volpert OV, Lawler J, Bouck NP . (1998). Proc Natl Acad Sci USA 95: 6343–6348.

  • Xu Y, Liu YJ, Yu Q . (2004a). Cancer Res 64: 6119–6126.

  • Xu Y, Liu YJ, Yu Q . (2004b). J Biol Chem 279: 41179–41188.

  • Xu Y, Yu Q . (2003). J Biol Chem 278: 8661–8668.

  • Yamazaki S, Iwamoto R, Saeki K, Asakura M, Takashima S, Yamazaki A et al. (2003). J Cell Biol 163: 469–475.

  • Yarden Y, Sliwkowski MX . (2001). Nat Rev Mol Cell Biol 2: 127–137.

  • Yee KO, Streit M, Hawighorst T, Detmar M, Lawler J . (2004). Am J Pathol 165: 541–552.

  • Yi M, Ruoslahti E . (2001). Proc Natl Acad Sci USA 98: 620–624.

  • Yu Q, Stamenkovic I . (1999). Genes and Dev 13: 35–48.

  • Yu Q, Stamenkovic I . (2000). Genes and Dev 14: 163–176.

  • Yu Q, Toole BP, Stamenkovic I . (1997). J Exp Med 186: 1985–1996.

Download references

Acknowledgements

We thank Dr Deborah McClellan for excellent editorial assistance. This work was supported by a fund from NIH (RO1HL074117).

Author information

Author notes

  1. Y-j Liu and Y Xu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Y-j Liu, Y Xu & Q Yu

Authors
  1. Y-j Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Q Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Q Yu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Yj., Xu, Y. & Yu, Q. Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively. Oncogene 25, 2452–2467 (2006). https://doi.org/10.1038/sj.onc.1209287

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209287

Keywords

This article is cited by

Search

Advanced search

Quick links