A Large Bioactive BMP Ligand with Distinct Signaling Properties Is Produced by Alternative Proconvertase Processing
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA. Science Signaling
(Impact Factor: 6.28).
04/2012; 5(218):ra28. DOI: 10.1126/scisignal.2002549
Dimers of conventional transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) ligands are composed of two 100- to 140-amino acid peptides that are produced through the proteolytic processing of a proprotein precursor by proconvertases, such as furin. We report the identification of an evolutionarily conserved furin processing site in the amino terminus (NS) of the Glass bottom boat (Gbb; the Drosophila ortholog of vertebrate BMP5, 6, and 7) proprotein that generates a 328-amino acid, active BMP ligand distinct from the conventional 130-amino acid ligand. Gbb38, the large ligand form of Gbb, exhibited greater signaling activity and a longer range than the shorter form Gbb15. The abundance of Gbb15 and Gbb38 varied among different tissues, raising the possibility that differential processing could account for tissue-specific behaviors of BMPs. In human populations, mutations that abolished the NS cleavage site in BMP4, BMP15, or anti-Müllerian hormone were associated with cleft lip with or without cleft palate (BMP4), premature ovarian failure (BMP15), and persistent Müllerian duct syndrome (anti-Müllerian hormone), suggesting the importance of NS processing during development. The identification of this large BMP ligand form and the functional differences between large and small ligands exemplifies the potential for differential proprotein processing to substantially affect BMP and TGF-β signaling output in different tissue and cellular contexts.
Available from: Christian Wegener
- "(see 3.3). In contrast, the role of dFURINS in processing bone morphogenetic protein signals (Glass bottom boat, Screw) is well investigated    "
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ABSTRACT: More than a decade has passed since the release of the Drosophila genome and the first predictions of fruit fly regulatory peptides (neuropeptides and peptide hormones). Since then, mass spectrometry-based methods have fuelled the chemical characterisation of regulatory peptides, from 7 Drosophila regulatory peptides in the pre-genomic area to around 60 today. We here review the development of fruit fly peptidomics, present a comprehensive list of the regulatory peptides that have been chemically characterised until today. We also summarise the knowledge on peptide processing in Drosophila, which has strongly profited from a combination of MS-based techniques and the genetic tools available for the fruit fly. This combination has a very high potential to study the functional biology of peptide signalling on all levels, especially with the ongoing developments in quantitative MS in Drosophila.
Available from: ncbi.nlm.nih.gov
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ABSTRACT: Over the past decade, rapid signal exchange between astroglia and neurons across the interstitial space emerged as an essential element of synaptic circuit functioning in the brain. How and where exactly this exchange occurs in various physiological scenarios and the underlying cellular cascades remain a subject of intense study. The excitatory neurotransmitter glutamate and the inhibitory neurotransmitter γ-aminobutyric acid are thought to be the primary signal carriers that are regularly dispatched by active synapses to engage target receptors and transporters on the surface of astrocytes. New evidence identifies another ubiquitous messenger, extracellular calcium ions (Ca(2+)), which can report neural network activity to astroglia. Astrocytes in the hippocampus can respond to activity-induced partial Ca(2+) depletion in the extracellular space by generating prominent intracellular Ca(2+) waves. The underlying Ca(2+) sensing mechanism is proposed to involve the opening of the hemichannel connexin 43 in astrocytes, which in turn triggers the release of adenosine triphosphate to boost the activity of inhibitory interneurons, thus potentially providing negative feedback to tame excessive excitatory activity of neural circuits.
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ABSTRACT: Signaling molecules of the transforming growth factor (TGF)-β family are generated from proprotein precursors containing prodomain sequences that are typically removed to allow signaling by the mature ligands. A form of a TGF-β family ligand that remains covalently attached to its prodomain but retains signaling activity has been identified. Glass bottom boat (Gbb), a Drosophila homolog of the bone morphogenetic protein 5/6/7/8 subfamily, is active as a carboxyl-terminal fragment of the proprotein (Gbb15) that is generated by a conventional processing event common to TGF-β ligands. Unexpectedly, a larger form (Gbb38) produced by processing at a newly identified furin site in the prodomain is also secreted and active. Contrary to the present paradigm in which TGF-β ligands require dissociation of the entire prodomain for activity, Gbb38 is active in cell culture and in vivo without additional processing at conventional sites. The large form can restore the viability of gbb mutant animals but has distinct signaling properties compared with the conventional form. Production of multiple functional ligands from one proprotein is a potential mechanism to fine-tune TGF-β signaling outputs. Mutations in TGF-β family members have been linked to human diseases, several of which affect potential furin cleavage sites in prodomains. However, given the diversity of potential furin processing sites and prodomain functions, direct experimentation will be required to determine whether production of active jumbo ligands is a general feature of TGF-β superfamily members.
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