2006 Fiscal Year Final Research Report Summary
Analysis of novel substrate for MT1-MMP and its cellular functions
| Project/Area Number |
17590336
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KOSHIKAWA Naohiko Univ. of Tokyo, Inst. of Med.Sci., Research Associate, 医科学研究所, 助手 (70334282)
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| Project Period (FY) |
2005 – 2006
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| Keywords | MT1-MMP / HB-EGF / EGF-R / Heparin-binding domain |
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| Research Abstract |
Heparin-binding EGF-like growth factor(HB-EGF) is synthesized as membrane-anchored proHB-EGF and it is converted to a soluble form(sHB-EGF) through processing at the membrane proximal region by proteases belonging to the ADAM(a disintegrin and metalloprotease) family. Additionally, the N-terminal region of proHB-EGF is also processed and multiple forms of proHB-EGFs have been observed. However, the proteinases responsible for processing of the N-terminal region and the effect of this processing on the HB-EGF activity are unknown. In this study we demonstrate that the N-terminal processing of proHB-EGF is defective in MT1-MMP-null fibroblasts and it was reconstituted by re-expression of MT1-MMP. The cleaved site by MTI-MMP in vitro was determined to be ^<82>A-^<83>L, but the N-terminus of the processed proHB-EGF in cells was five amino acid downstream(^<88>K). Corresponding sHB-EGFs were also detected in the culture medium. Although the processed proHB-EGF by MT1-MMP still retains the basic amino acid stretch for heparin binding, it did not bind to a heparin column. Processing of proHB-EGF by MT1-MMP was also sufficient to convert the heparin dependent mitogenic activity to independent. These results indicate that MT1-MMP is a critical new regulator of HB-EGF as it converts HB-EGF from a heparin-dependent to an independent growth factor.
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