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Journal of Biochemistry 2005 137(1):95-99; doi:10.1093/jb/mvi009
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© 2005 The Japanese Biochemical Society

BIOCHEMISTRY

Cleavage of Apolipoprotein E by Membrane-Type Matrix Metalloproteinase-1 Abrogates Suppression of Cell Proliferation

Takanori Aoki1,2, Daisuke Sato1, Yingyi Li1, Takahisa Takino1, Hisashi Miyamori1 and Hiroshi Sato1,3,*

1 Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934; 2 Daiichi Fine Chemical Co. Ltd., 530 Chokeiji, Takaoka, Toyama 933-8511; and 3 Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934

Apolipoprotein E (apoE) in a human fetal brain cDNA library was identified, using the expression cloning method, as a gene product that formed a complex with latent matrix metalloproteinase (MMP)-2. Co-expression of membrane-type MMP-1 (MT1-MMP) with apoE in HEK293T cells reduced the amount of apoE secreted into the culture medium, whereas cell-associated apoE core protein was not affected. Incubation of native apoE protein with recombinant MT1-MMP resulted in the cleavage of apoE. Recombinant apoE protein fused to glutathione S-transferase (apoE-GST) was cleaved by MT1-MMP at the following peptide bonds; T85-M86, K93-S94, R246-L247, A255-E256 and G296-L297. HT1080 cells transfected with the apoE gene, which express endogenous MT1-MMP, secreted a low level of apoE protein and its cleaved fragments, and treatment with MMP inhibitor BB94 induced accumulation of apoE and retardation of cell proliferation. Addition of apoE-GST protein to the culture of HEK293T cells suppressed cell proliferation, and stable transfection of the MT1-MMP gene partly abrogated the suppression. These results suggest that cleavage of apoE protein by MT1-MMP abrogates apoE-mediated suppression of cell proliferation.

* To whom correspondence should be addressed at: Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934. Tel: +81-76-265-2749, Fax: +81-76-234-4505, E-mail: vhsato{at}kenroku.kanazawa-u.ac.jp


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