Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency

Lee, Wing C.; Almeida, Sandra; Prudencio, Mercedes; Caulfield, Thomas R.; Zhang, Yong Jie; Tay, William M.; Bauer, Peter; Chew, Jeannie; Sasaguri, Hiroki; Jansen-West, Karen; Gendron, Tania F.; Stetler, Caroline; Finch, Ni Cole A.; Mackenzie, Ian R.; Rademakers, Rosa; Gao, Fen Biao; Petrucelli, Leonard

doi:10.1093/hmg/ddt534

Cited by 104 publications

(85 citation statements)

References 49 publications

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“…In neurons, sortilin has been shown to promote rapid progranulin endocytosis and subsequent lysosomal degradation (11,15). However, the pathways by which sortilin mediates progranulin clearance from the medium and internalization from the cell membrane have not been characterized.…”

Section: Characterization Of Progranulin Endocytosis and Sorting In Pmentioning

confidence: 99%

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Sortilin Regulates Progranulin Action in Castration-Resistant Prostate Cancer Cells

et al. 2015

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The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.

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Section: Characterization Of Progranulin Endocytosis and Sorting In Pmentioning

confidence: 99%

“…Notably, progranulin levels are significantly decreased in sortilin knockout mice (11). Reduced progranulin levels are associated with frontotemporal dementia similarly to haploinsufficiency associated with progranulin gene mutations (13,14), and targeted manipulation of the sortilin/progranulin axis rescues progranulin haploinsufficiency (15).…”

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confidence: 99%

Sortilin Regulates Progranulin Action in Castration-Resistant Prostate Cancer Cells

et al. 2015

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“…Reduced progranulin levels are associated with frontotemporal dementia similarly to haploinsufficiency associated with progranulin gene mutations [59,60] and targeted manipulation of the sortilin/progranulin axis rescues progranulin haploinsufficiency [61].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Tanimoto

Palladino

et al. 2017

Matrix Biology

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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.

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“…The neurons were found to be more susceptible to cellular stress and oxidative stress compared to control neurons, which could be reversed upon induced expression of GRN [66]. A follow-up study on the same neurons used these neurons to test different approaches of rescuing GRN expression as a way of finding new tools to treat the disease [78].…”

Section: Grn Mutationsmentioning

confidence: 99%

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

Hall¹

2016

Pluripotent Stem Cells - From the Bench to the Clinic

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Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer's disease, frontotemporal dementia and Parkinson's disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only some of the phenotype can be observed in-vitro, but these phenotypes, when compared to the patient, correlate extremely well. Many studies have found novel molecular mechanisms involved in the disease and therefore elucidate new potential targets for reversing the phenotype. Future research that includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about these diseases, but will lead to even more findings in the future as gene and cell culture technology continues to develop.

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Targeted manipulation of the sortilin–progranulin axis rescues progranulin haploinsufficiency

Cited by 104 publications

References 49 publications

Sortilin Regulates Progranulin Action in Castration-Resistant Prostate Cancer Cells

Sortilin Regulates Progranulin Action in Castration-Resistant Prostate Cancer Cells

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

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

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