The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth
Human patients carrying PAPP-A2 inactivating mutations display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report that Papp-aa regulates bone calcification via promoting Ca2+-transporting epithelial cell (ionocyte) reactivation and proliferation. Ionocyte, normally quiescent, proliferate in response to low [Ca2+] stress. Deletion of Papp-aa abolished ionocyte reactivation and reduced calcified bone mass. Loss of Papp-aa resulted in diminished IGF1 receptor-mediated Akt-Tor signaling in ionocytes. Re-expression of Papp-aa or a constitutively active Akt in ionocytes rescued the reactivation. Biochemically, Papp-aa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. The Papp-aa-mediated Igfbp5a proteolysis was suppressed under normal [Ca2+] conditions. Forced release of IGFs from the Igfbp5a/IGF complex was sufficient to activate IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca2+]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.
- Downloaded 382 times
- Download rankings, all-time:
- Site-wide: 100,232
- In developmental biology: 2,697
- Year to date:
- Site-wide: 139,023
- Since beginning of last month:
- Site-wide: 142,187
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!