Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases

Takahisa Takino; Naohiko Koshikawa; Hisashi Miyamori; Motohiro Tanaka; Takuma Sasaki; Yasunori Okada; Motoharu Seiki; Hiroshi Sato

doi:10.1038/sj.onc.1206542

Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases

Takahisa Takino, Naohiko Koshikawa, Hisashi Miyamori, Motohiro Tanaka, Takuma Sasaki, Yasunori Okada, Motoharu Seiki, Hiroshi Sato

Research output: Contribution to journal › Article › peer-review

126 Citations (Scopus)

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 Gly ¹¹⁸-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.

Original language	English
Pages (from-to)	4617-4626
Number of pages	10
Journal	Oncogene
Volume	22
Issue number	30
DOIs	https://doi.org/10.1038/sj.onc.1206542
Publication status	Published - 2003 Jul 24
Externally published	Yes

Keywords

Cleavage
KiSS-1
MMP

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/sj.onc.1206542

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title = "Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases",

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 Gly 118-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.",

keywords = "Cleavage, KiSS-1, MMP",

author = "Takahisa Takino and Naohiko Koshikawa and Hisashi Miyamori and Motohiro Tanaka and Takuma Sasaki and Yasunori Okada and Motoharu Seiki and Hiroshi Sato",

note = "Funding Information: We thank EW Thompson (St Vincent{\textquoteright}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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AU - Takino, Takahisa

AU - Koshikawa, Naohiko

AU - Miyamori, Hisashi

AU - Tanaka, Motohiro

AU - Sasaki, Takuma

AU - Okada, Yasunori

AU - Seiki, Motoharu

AU - Sato, Hiroshi

N1 - Funding Information: 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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N2 - 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 Gly 118-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.

AB - 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 Gly 118-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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JF - Oncogene

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ER -

Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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