| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) superfamily, were originally identified as osteoinductive proteins in bone that induce ectopic bone and cartilage formation in vivo. BMPs bind to type I and type II serine/threonine kinase receptors, BMPR-I and II. Smad proteins play central roles in intracellular signaling by BMPs. Eight different Smad proteins have been identified in mammals, and are classified into three subgroups, i. e. receptor-regulated Smads (R-Smads), a common-partner Smad (Co-Smad), and inhibitory Smads (I-Smads). BMP-specific R-Smads, Smads 1,5 and 8, transiently and directly interact with activated BMPR-Is, and become phosphorylated. Smad1/5/8 then form heteromeric complexes with Co-Smad, Smad4, and translocate into the nucleus where they regulate transcription of various target genes. In contrast, I-Smads, including Smad6 and Smad7, stably bind to BMPR-Is and compete with Smad1/5/8 for activation, resulting in inhibition of BMP signaling.
In this project, we examined the function of Smad ubiquitin regulatory factor(Smurf) 1 as a Smad binding protein. Smurf1 was originally identified as an E3 ubiquitin ligase for Smad1/5. We demonstrated that Smurf1 associates with type I receptors for BMPs through the I-Smads, and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.
Next, we clarified the mechanism of nuclear export and membrane localization of Smurf1-I-Smad complex. Smurf1 binds to CRM1, and Smurf1-I-Smad complex translocates from the nucleus to the cytoplasm. Then Smurf1-I-Smad complex locates to cell membrane through C2 domain of Smurf1.
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