| Budget Amount *help |
¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
Activin signal transduction is regulated through multiple mechanisms. We have identified novel regulatory proteins that control activin functions either intracellularly or extracellularly. As intracellular molecules, PDZ (PSD-95/Dlg/ZO-1) proteins that specifically associate with activin type II receptors (ActRIIs) were identified. We have named the molecules as ARIPs (activin receptor-interacting proteins). ARIP1 has two WW domains at its NH2 terminus and five PDZ domains at its COOH-terminus. ARIP1 associated with Smad proteins via WW domains and associated with ActRIIAs via PDZ domain 5. ARIP1 can recruite Smad 3 as well as binding to activin receptors, thus ARIP1 may be the scaffold of the activin-signaling complex in the cell membrane and in the submembranous region, and participate in a physiological regulation of signal transduction. In accord with this speculation, we have observed that overexpression of ARIP1 suppressed Smad 3-augmented transcription in a mouse hippocampus-derived cells and inhibited Smad 3 nuclear translocation by ligand stimulation. ARIPs are likely to have a role of assembling and/or transporting of activin receptors.
As an extracellular regulatory protein, we have identified a novel follistatin-like protein, named FLRG (follistatin-related gene). Like follistatins, FLRG binds activins and BMPs (bone morphogenetic proteins) and controls their functions extracellularly. Interestingly, FLRG contains only two follistatin domains, and second follistatin domain including COOH-terminal acidic region is able to bind activin. This mode of association is different from that of follistatin-activin. Since follistatin and FLRG are expressed in a different manner and they are likely to be local regulators of activin and BMPs, their functions in vivo are likely to be different. Specific monoclonal antibodies recognizing mouse and human FLRG have been made to characterize the functions of FLRG further.
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