Proteolytic control of TGF-β co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics

The metalloproteinase BMP-1 (bone morphogenetic protein-1) plays a major role in the control of extracellular matrix (ECM) assembly and growth factor activation. Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi: 10.6019/PXD000786.     

A new species of Austrorhynchus (Platyhelminthes: Kalyptorhynchia) from King George Island (Maritime Antarctic)

A new species of the turbellarian genus Austrorhynchus (Kalyptorhynchia: Polycystididae) was found in King George Island (South Shetland Islands, Maritime Antarctic). The new species has eyes and white to greyish parenchyma. The type II prostate stylet has a funnel and a slightly bent tube with an inner stylet extending throughout its length; a strongly bent hook of about the same size as the tube is present. The type III prostate stylet has a foot and a style connected by a bridge, defining a broad window; the style expands to a comb-bearing plate with large teeth; the foot continues into a narrow flagellum with a distal expansion and a row of fine teeth. The species is oviparous. It can be distinguished from the other known Austrorhynchus species by the shape and size of the type II and type III prostate stylets. Out of the five known species of Austrorhynchus presenting a window in the type III stylet, the four more similar ones are found in the northern arm of the Scotia Arc and the Weddell Sea area. This is the first report of Kalyptorhynchia from the Antarctic portion of the Scotia Sea, and it confirms previous observations that the true number of Austrorhynchus species in the area must be higher than what is currently known.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:098ADF23-763B-41F6-A2F5-54F6AA8620E8     

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.