Regulation of signal transduction of TGF-β family by novel adaptor and binding proteins

点击翻译按钮获取中文摘要

We have analyzed the regulation of myostatin and activin signaling by receptor associated adaptor proteins and binding proteins. Myostatin and activin belong to the TGF-β superfamily and signal through activin type II receptors (ActRIIs) that are receptor serine/threonine kinases. ActRIIs are unique among other receptor serine kinases for the TGF-β family in that they have consensus binding motifs for PDZ proteins at their carboxy terminus. We have identified multiple PDZ proteins, called activin receptor-interacting proteins (ARIPs) that associate with ActRIIs. ARIP1 is a large protein having five PDZ domains and two WW domains, and associates not only with ActRIIs but also with glutamate receptors and src family of tyrosine kinases. ARIP2 is a small protein that has only one PDZ domain. We have identified ARIP2 has at least four splicing variants, ARIP2, 2b, 2c and OMP25 that are formed by alternative RNA splicing events from one gene. Whereas ARIP2 enhances endocytosis of ActRII thr … More ough Ral/RalBP1-dependent pathway and inhibit activin/myostatin signaling, ARIP2b and 2c do not associate with RalBP1. ARIP 2b/2c increase cell surface level of ActRIIs and augment signaling.We also analyzed follistatin and FLRG that are binding proteins for myostatin and activin. Like follistatin, FLRG is expressed in uterus and placenta, but mode of regulation of FLRG expression by sex steroids are different from that of follistatin. In mouse skeletal muscles, FLRG is specifically expressed in slow type muscle fibers. FLRG is likely to regulate myostatin activity in serum as well as in skeletal muscle tissues locally. We have made various artificial protein derived from follistatin, and identified several myostatin-specific inhibitors. We have made transgenic mouse that overexpress one of myostatin-specific inhibitors. The mice show increase of skeletal muscle mass. When crossed with mdx dystrophy model mice, pathological changes such as fibrosis and fatty remodeling seen in mdx mice were prevented, suggesting that our myostatin inhibitors would be a good drugs for treatment of muscular dystrophy and other muscle-wasting disorders. Less