1996 Fiscal Year Final Research Report Summary
The establishment of screening system to identify compoundsthat target BMP receptor-associated molecules
| Project/Area Number |
07557373
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 試験 |
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| Research Field |
Biological pharmacy
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
UENO Naoto Hokkaido Univ., Fac of pharmaceutical Science, Pro., 薬学部, 教授 (40221105)
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| Co-Investigator(Kenkyū-buntansha) |
KATSUMATA Takashi Sumitomo Pharm.Inc., 総合研究所, 主任研究員
SHIBUYA Hiroshi Hokkaido Univ., Fac of pharmaceutical Science Assistant Professor, 薬学部, 助教授 (30261324)
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| Project Period (FY) |
1995 – 1996
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| Keywords | BMP / bone formation / receptor / Ser / Thr kinase / Signal transduction |
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| Research Abstract |
In order to develop efficienct drugs that mimic the endogenous pathway of cytokines, precise molecular mechanism of signal transduction has to be clarified. Based on the mechanism, screening for compunds that modify the signaling pathway and thus act as agonist or antagonist can be achieved. TGF-beta activating kinase 1 (TAK1) and its activator, TAK1 binding protein 1 (TAB1) are implicated in TGF-beta and bone morphogenetic protein (BMP) signaling. However, the precise molecular mechanism by which ligand-ligated type I receptors induce TAB1 to activate TAK1 remains to be identified. To clarify BMP receptor mediated signaling, cytoplasmic interactors of BMP type Ia receptor (BMPRIa) were isolated with the use of a yeast two-hybrid system. One of the interactors isolated bound both TAB1 and BMPRIa in vivo. Sequence analysis revealed that this clone encoded a previously identified a denovirus E1A-associated protein, BS69. Although it contained E1A binding domain of BS69, NH2-terminal 12 amino acids of this clone were different from corresponding region of BS69. Therefore, we designated this molecule as BMP receptor associated molecule2 (BRAM2) and used in further experiments. The BRAM2 bound BMPRIa and TGF-beta type I receptor (TbetaRI) and augmented TAB1 binding to BMPRIa and TbetaRI in vivo. Furthermore, TAK1 and TAB1 mediated activation of plasminogen activator inhibitor-1 (PAI-1) gene promoter was strength ened by the expression of BRAM2. These results suggest that BRAM2 regulates the activity of TAB1 and is involved in TGF-beta and BMP signaling. Based on this knowledge, compunds that stimulate binding of BRAM2 to BMPR and may serve as agonists can now be screeened.
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Research Products
(12 results)
