The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin

Abstract

Despite 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-à-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 feed-back mechanism whereby sortilin downregulation ensures sustained progranulin-mediated oncogenesis.

Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion

“…5b and Additional file 1 : Figure S5B). Further, immunohistochemical staining of the xenografts showed a decreased expression of sortilin after GRN A injections as well as in combination with AF38469 treatment (Additional file 1 : Figure S5C), demonstrating that GRN A induces degradation of SORT1 similar to what has been shown with full-length progranulin [ 27 ]. Moreover, MDA-MB 231-luc xenografts grew highly infiltrative and produced ulcerations and skin infiltration in a large fraction of the control and GRN A-treated animals (Fig.…”

Matrix modeling and remodeling: A biological interplay regulating tissue homeostasis and diseases

“…Structurally, perlecan augments cellular adhesion and co-localizes with laminins, specifically laminin 322, to further stabilize keratinocyte attachment. Primarily, perlecan functions as a repository for HS-binding growth factors whereupon degradation of the its HS chains or perlecan itself releases the pleiotropic growth factor progranulin [121,122] as well as other mitogens and trophic factors necessary for the reparative process. Supporting this concept, transgenic mice lacking these HS chains have delayed wound healing and decreased vascular density, despite maintaining wound closure rates [123].…”

Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway

“…Reducing sortilin levels increases levels of extracellular progranulin in neurons. Interestingly, progranulin itself regulates sortilin degradation and thus may regulate its own levels in an autocrine fashion to maintain the pathogenic progression of prostate cancer (Tanimoto et al, 2017). Similarly, prosaposin (PSAP) binds and targets extracellular progranulin to lysosomes; suppression of PSAP increased progranulin levels in neurons .…”