Journal
GROWTH FACTORS
Volume 29, Issue 5, Pages 174-186Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/08977194.2011.608666
Keywords
Transforming growth factor beta; activin; inhibin; bone morphogenetic protein; growth differentiation factor; prodomain
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Funding
- National Health and Medical Research Council of Australia [1006488, 241000]
- NHMRC
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All transforming growth factor-beta (TGF-beta) ligands are synthesised as precursor molecules consisting of a signal peptide, an N-terminal prodomain and a C-terminal mature domain. During synthesis, prodomains interact non-covalently with mature domains, maintaining the molecules in a conformation competent for dimerisation. Dimeric precursors are cleaved by proprotein convertases, and TGF-beta ligands are secreted from the cell non-covalently associated with their prodomains. Extracellularly, prodomains localise TGF-beta ligands within the vicinity of their target cells via interactions with extracellular matrix proteins, including fibrillin and perlecan. For some family members (TGF-beta 1, TGF-beta 2, TGF-beta 3, myostatin, GDF-11 and BMP-10), prodomains bind with high enough affinity to suppress biological activity. The subsequent mechanism of activation of these latent TGF-beta ligands varies according to cell type and context, but all activating mechanisms directly target prodomains. Thus, prodomains control many aspects of TGF-beta superfamily biology, and alterations in prodomain function are often associated with disease.
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