Abstract
A human placenta cDNA library was screened by the expression cloning method for gene products that interact with matrix metalloproteinases (MMPs), and we isolated a cDNA whose product formed a stable complex with pro-MMP-2 and pro-MMP-9. The cDNA encoded the metastasis suppressor gene KiSS-1. KiSS-1 protein was shown to form a complex with pro-MMP. KiSS-1 protein is known to be processed to peptide ligand of a G-protein-coupled receptor (hOT7T175) named metastin, and suppresses metastasis of tumors expressing the receptor. Active MMP-2, MMP-9, MT1-MMP, MT3-MMP and MT5-MMP cleaved the Gly118-Leu119 peptide bond of not only full-length KiSS-1 protein but also metastin decapeptide. Metastin decapeptide induced formation of focal adhesion and actin stress fibers in cells expressing the receptor, and digestion of metastin decapeptide by MMP abolished its ligand activity. Migration of HT1080 cells expressing hOT7T175 that harbor a high-level MMP activity was only slightly suppressed by either metastin decapeptide or MMP inhibitor BB-94 alone, but the combination of metastin decapeptide and BB-94 showed a synergistic effect in blocking cell migration. We propose that metastin could be used as an antimetastatic agent in combination with MMP inhibitor, or MMP-resistant forms of metastin could be developed and may also be efficacious.
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References
Birkedal HH, Moore WG, Bodden MK, Windsor LJ, Birkedal HB, DeCarlo A and Engler JA . (1993). Crit. Rev. Oral Biol. Med., 4, 197–250.
Fowlkes JL, Enghild JJ, Suzuki K and Nagase H . (1994). J. Biol. Chem., 269, 25742–25746.
Gearing AJ, Beckett P, Christodoulou M, Churchill M, Clements J, Davidson AH, Drummond AH, Galloway WA, Gilbert R and Gordon JL . (1994). Nature, 370, 555–557.
Hiller O, Lichte A, Oberpichler A, Kocourek A and Tschesche H . (2000). J. Biol. Chem., 275, 33008–33013.
Ito A, Mukaiyama A, Itoh Y, Nagase H, Thogersen IB, Enghild JJ, Sasaguri Y and Mori Y . (1996). J. Biol. Chem., 271, 14657–14660.
Jaworski DM . (2000). Brain Res., 860, 174–177.
Kinoshita T, Sato H, Okada A, Ohuchi E, Imai K, Okada Y and Seiki M . (1998). J. Biol. Chem., 273, 16098–16103.
Knight CG, Willenbrock F and Murphy G . (1992). FEBS Lett., 296, 263–266.
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G and Parmentier M . (2001). J. Biol. Chem., 276, 34631–34636.
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE and Welch DR . (1996). J. Natl. Cancer Inst., 88, 1731–1737.
Lee JH and Welch DR . (1997). Int. J. Cancer, 71, 1035–1044.
Lee JH, Welch DR and Patt WC . (1997). Cancer Res., 57, 2384–2387.
Levi E, Fridman R, Miao HQ, Ma YS, Yayon A and Vlodavsky I . (1996). Proc. Natl. Acad. Sci. USA, 93, 7069–7074.
Llano E, Pendas AM, Freije JP, Nakano A, Knauper V, Murphy G and Lopez-Otin C . (1999). Cancer Res., 59, 2570–2576.
McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I and Overall CM . (2001). J. Biol. Chem., 276, 43503–43508.
McQuibban GA, Gong JH, Tam EM, McCulloch CA, Clark-Lewis I and Overall CM . (2000). Science, 289, 1202–1206.
McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I and Overall CM . (2002). Blood, 100, 1160–1167.
Miyamori H, Takino T, Kobayashi Y, Tokai H, Itoh Y, Seiki M and Sato H . (2001). J. Biol. Chem., 276, 28204–28211.
Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL and Harrison DC . (2001). J. Biol. Chem., 276, 28969–28975.
Murray MJ and Lessey BA . (1999). Semin. Reproductive Endocrinol., 17, 275–290.
Nagase H and Woessner Jr JF . (1999). J. Biol. Chem., 274, 21491–21494.
Nakada M, Yamada A, Takino T, Miyamori H, Takahashi T, Yamashita J and Sato H . (2001). Cancer Res., 61, 8896–8902.
Nomura H, Sato H, Seiki M, Mai M and Okada Y . (1995). Cancer Res., 55, 3263–3266.
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O and Fujino M . (2001). Nature, 411, 613–617.
Pei D . (1999). J. Biol. Chem., 274, 8925–8932.
Powell WC, Fingleton B, Wilson CL, Boothby M and Matrisian LM . (1999). Curr. Biol., 9, 1441–1447.
Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E and Seiki M . (1994). Nature, 370, 61–65.
Seiki M . (1999). Apmis, 107, 137–143.
Shimada T, Nakamura H, Ohuchi E, Fujii Y, Murakami Y, Sato H, Seiki M and Okada Y . (1999). Eur. J. Biochem., 262, 907–914.
Shirasaki F, Takata M, Hatta N and Takehara K . (2001). Cancer Res., 61, 7422–7425.
Stetler-Stevenson WG, Aznavoorian S and Liotta LA . (1993). Annu. Rev. Cell Biol., 9, 541–573.
Suzuki M, Raab G, Moses MA, Fernandez CA and Klagsbrun M . (1997). J. Biol. Chem., 272, 31730–31737.
Takino T, Sato H, Shinagawa A and Seiki M . (1995). J. Biol. Chem., 270, 23013–23020.
Ueno H, Nakamura H, Inoue M, Imai K, Noguchi M, Sato H, Seiki M and Okada Y . (1997). Cancer Res., 57, 2055–2060.
Van den Steen PE, Proost P, Wuyts A, Van Damme J and Opdenakker G . (2000). Blood, 96, 2673–2681.
Velasco G, Cal S, Merlos-Suarez A, Ferrando AA, Alvarez S, Nakano A, Arribas J and Lopez-Otin C . (2000). Cancer Res., 60, 877–882.
Woessner JJ and Gunja SZ . (1991). J. Rheumatol Suppl., 27, 99–101.
Yan C, Wang H and Boyd DD . (2001). J. Biol. Chem., 276, 1164–1172.
Acknowledgements
We thank EW Thompson (St Vincent's Institute of Medical Research) for critical reading of the manuscript. This work was supported in part by Grant-in-Aid for Scientific Research on Priority Areas (HS and TT) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Takino, T., Koshikawa, N., Miyamori, H. et al. Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases. Oncogene 22, 4617–4626 (2003). https://doi.org/10.1038/sj.onc.1206542
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DOI: https://doi.org/10.1038/sj.onc.1206542
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