Regulation of myostatin in vivo by growth and differentiation factor-associated serum protein-1: a novel protein with protease inhibitor and follistatin domains.
Myostatin, a member of the TGFbeta superfamily, is a potent and specific negative regulator of skeletal muscle mass. In serum, myostatin circulates as part of a latent complex containing myostatin propeptide and/or follistatin-related gene (FLRG). Here, we report the identification of an additional protein associated with endogenous myostatin in normal mouse and human serum, discovered by affinity purification and mass spectrometry. This protein, which we have named growth and differentiation factor-associated serum protein-1 (GASP-1), contains multiple domains associated with protease-inhibitory proteins, including a whey acidic protein domain, a Kazal domain, two Kunitz domains, and a netrin domain. GASP-1 also contains a domain homologous to the 10-cysteine repeat found in follistatin, a protein that binds and inhibits activin, another member of the TGFbeta superfamily. We have cloned mouse GASP-1 and shown that it inhibits the biological activity of mature myostatin, but not activin, in a luciferase reporter gene assay. Surprisingly, recombinant GASP-1 binds directly not only to mature myostatin, but also to the myostatin propeptide. Thus, GASP-1 represents a novel class of inhibitory TGFbeta binding proteins.
Hill
Jennifer J
JJ
Department of Protein Chemistry and Proteomics, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. jhill@wyeth.com.
Qiu
Yongchang
Y
Hewick
Rodney M
RM
Wolfman
Neil M
NM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D055435:Myostatin; D011480:Protease Inhibitors / Q000097:blood / Q000302:isolation & purification* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*
D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C525911:MSTN protein, human; C525912:Mstn protein, mouse; D055435:Myostatin; D011480:Protease Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta