Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinases.
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.
Takino
Takahisa
T
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
Koshikawa
Naohiko
N
Miyamori
Hisashi
H
Tanaka
Motohiro
M
Sasaki
Takuma
T
Okada
Yasunori
Y
Seiki
Motoharu
M
Sato
Hiroshi
H
D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D059648:Kisspeptins; D008024:Ligands; D008164:Luminescent Proteins; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018076:DNA, Complementary; C106628:KISS1 protein, human; D059648:Kisspeptins; D008024:Ligands; D008164:Luminescent Proteins; D010455:Peptides; D011506:Proteins; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9