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

摘要: Despite extensive clinical and experimental studies over the past decades, pathogenesis progression to castration-resistant stage of prostate cancer remains largely unknown. Progranulin, a secreted growth factor, strongly binds heparin-sulfate proteoglycan perlecan, counteracts its biological activity. We established that progranulin acts as an autocrine factor promotes cell motility, invasion, anchorage-independent growth. Progranulin was overexpressed in tissues vis-a-vis non-neoplastic supporting hypothesis may play key role progression. However, progranulin's mode action is not well understood proteins regulating signaling have been identified. Sortilin, single-pass type I transmembrane protein Vps10 family, neurons targets for lysosomal degradation. Significantly, DU145 PC3 cells, we detected very low levels sortilin associated with high production enhanced motility. Restoring expression decreased levels, inhibited motility destabilized Akt. These results demonstrated critical suggest loss contribute Here, provide novel observation downregulated independent transcription. induced ubiquitination, internalization via clathrin-dependent endocytosis sorting into early endosomes Collectively, these constitute regulatory feed-back mechanism whereby downregulation ensures sustained progranulin-mediated oncogenesis.