2002 Fiscal Year Final Research Report Summary
Regulatory Roles of Meltrins, Members of ADAM Proteases, in Cell-cell Internation
| Project/Area Number |
11235203
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University (2000-2003)
Tokyo Metropolitan Organization for Medical Research (1999) |
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Principal Investigator |
ATSUKO Sehara-fujisawa Institute for Frontier Medical Sciences, Professor, 再生医科学研究所, 教授 (60209038)
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| Co-Investigator(Kenkyū-buntansha) |
TOMOHIRO Kurisaki Institute for Frontier Medical Sciences, Assistant, 再生医科学研究所, 助手 (90311422)
NAGASAWA Takashi NAGASAWA,Takashi (80281690)
BABA Tadashi University of Tsukuba, Institute of Applied Biochemistry, Professor (40165056)
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| Project Period (FY) |
2003
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| Keywords | ADAM / metalloprotease / ectodomain shedding / myogenesis / development / cardiogenesis / ErbB / growth factor |
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| Research Abstract |
ADAM (a disintegrin and metalloprotease) is a family of multidomain proteins that can modulate intercellular signaling. We found that Meltrin a and b (ADAM12 and ADAM19, respectively) proteases participate in the ectodomain shedding (proteolysis of membrane proteins at the extracellular juxta-membrane region) of HB-EGF and Neuregulin, respectively, both of which are membrane-anchored ligands for ErbB receptor tyrosine kinases. In the case of Meltrin b, one of the mechanisms specifying substrates is intracellular co-localization of Meltrin b and its substrate in cholesterol-rich microdomains in the lipid bilayer. To investigate roles of ADAM proteins and significance of their functions as proteases in development, we generated the knockout mice of Meltrin a and b genes. The phenotypes of these mice indicated that Meltrin a plays roles in muscle and brown adipose tissue development while Meltrin b participates in formation of the endocardial cushion that gives rise to valves and septum of the heart. Embryonic fibroblasts prepared from Meltrin a-or Melrin b-lacking mice have defects in phorbol ester-enhanced ectodomain shedding of membrane-anchored growth factors. In this project, we also identified a novel ADAM protease, Meltrin e, from a cDNA library prepared from myotomes. This is au epitheha-specific ADAM, and is prominently expressed in lens and otic placodes and in intestinal epitheha during development.
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