Show simple item record

dc.creatorTanimoto, Ryuta
dc.creatorPalladino, Chiara
dc.creatorXu, Shi-Qiong
dc.creatorBuraschi, Simone
dc.creatorNeill, Thomas
dc.creatorGomella, Leonard G.
dc.creatorPeiper, Stephen C.
dc.creatorBelfiore, Antonino
dc.creatorIozzzo, Renato V.
dc.creatorMorrione, Andrea
dc.date.accessioned2021-11-09T15:40:31Z
dc.date.available2021-11-09T15:40:31Z
dc.date.issued2017-04-20
dc.identifier.citationRyuta Tanimoto, Chiara Palladino, Shi-Qiong Xu, Simone Buraschi, Thomas Neill, Leonard G. Gomella, Stephen C. Peiper, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione, The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin, Matrix Biology,Volume 64, 2017, Pages 27-39, ISSN 0945-053X, https://doi.org/10.1016/j.matbio.2017.04.001.
dc.identifier.issn0945-053X
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/7060
dc.identifier.urihttp://hdl.handle.net/20.500.12613/7080
dc.description.abstractDespite extensive clinical and experimental studies over the past decades, the pathogenesis and progression to the castration-resistant stage of prostate cancer remains largely unknown. Progranulin, a secreted growth factor, strongly binds the heparin-sulfate proteoglycan perlecan, and counteracts its biological activity. We established that progranulin acts as an autocrine growth factor and promotes prostate cancer cell motility, invasion, and anchorage-independent growth. Progranulin was overexpressed in prostate cancer tissues vis-á-vis non-neoplastic tissues supporting the hypothesis that progranulin may play a key role in prostate cancer progression. However, progranulin's mode of action is not well understood and proteins regulating progranulin signaling have not been identified. Sortilin, a single-pass type I transmembrane protein of the Vps10 family, binds progranulin in neurons and targets progranulin for lysosomal degradation. Significantly, in DU145 and PC3 cells, we detected very low levels of sortilin associated with high levels of progranulin production and enhanced motility. Restoring sortilin expression decreased progranulin levels, inhibited motility and anchorage-independent growth and destabilized Akt. These results demonstrated a critical role for sortilin in regulating progranulin and suggest that sortilin loss may contribute to prostate cancer progression. Here, we provide the novel observation that progranulin downregulated sortilin protein levels independent of transcription. Progranulin induced sortilin ubiquitination, internalization via clathrin dependent endocytosis and sorting into early endosomes for lysosomal degradation. Collectively, these results constitute a regulatory feedback mechanism whereby sortilin downregulation ensures sustained progranulin-mediated oncogenesis.
dc.format.extent22 pages
dc.languageEnglish
dc.language.isoeng
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartMatrix Biology, Vol. 64
dc.relation.isreferencedbyElsevier
dc.relation.isreferencedby© 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rightsAttribution-NonCommercial-NoDerivs CC BY-NC-ND
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectProgranulin
dc.subjectSortilin
dc.subjectProstate cancer
dc.subjectCastration-resistant prostate cancer cells
dc.titleThe perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin
dc.typeText
dc.type.genrePost-print
dc.description.departmentBiology
dc.relation.doihttps://doi.org/10.1016/j.matbio.2017.04.001
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.schoolcollegeTemple University. College of Science and Technology
dc.creator.orcidMorrione|0000-0002-2319-7884
dc.temple.creatorMorrione, Andrea
refterms.dateFOA2021-11-09T15:40:31Z


Files in this item

Thumbnail
Name:
Morrione-Postprint-2017.pdf
Size:
1.314Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivs CC BY-NC-ND
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs CC BY-NC-ND