Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Schmidt, Vanessa; Willnow, Thomas E.

doi:10.1016/j.atherosclerosis.2015.11.027

Cited by 30 publications

(21 citation statements)

References 77 publications

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“…Among them, sortilin is implicated in atherosclerosis and atherosclerotic plaques development through multiple processes, including regulation of calcification (Goettsch et al, 2016), lipoprotein metabolism (Kjolby et al, 2010; Strong et al, 2012), Glut4 biogenesis and glucose uptake in type-2 diabetes (Shi and Kandror, 2005) and arterial wall inflammation (Mortensen et al, 2014; Patel et al, 2015). In this review we will only discuss the relationship between sortilin and the immune system in atherosclerosis (more details on the implication of sortilin in atherosclerosis can be found in recent reviews) (Schmidt and Willnow, 2016; Zhong et al, 2016; Goettsch et al, 2018).…”

Section: Sortilin Sorla and Inflammationmentioning

confidence: 99%

“…Moreover, SorLA has been described as a risk factor for obesity (Whittle et al, 2015; Schmidt et al, 2016). Both proteins are involved in cardiovascular and metabolic diseases, such as atherosclerosis and type-2 diabetes, because of their lipoproteins regulatory functions reviewed in (Schmidt and Willnow, 2016). Finally, sortilin has been shown to be implicated in the development of different cancers (Wilson et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

et al. 2019

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Sortilin, also known as Neurotensin Receptor-3, and the sorting-related receptor with type-A repeats (SorLA) are both members of the Vps10p domain receptor family. Initially identified in CNS cells, they are expressed in various other cell types where they exert multiple functions. Although mostly studied for its involvement in Alzheimer’s disease, SorLA has recently been shown to be implicated in immune response by regulating IL-6-mediated signaling, as well as driving monocyte migration. Sortilin has been shown to act as a receptor, as a co-receptor and as an intra- and extracellular trafficking regulator. In the last two decades, deregulation of sortilin has been demonstrated to be involved in many human pathophysiologies, including neurodegenerative disorders (Alzheimer and Parkinson diseases), type 2 diabetes and obesity, cancer, and cardiovascular pathologies such as atherosclerosis. Several studies highlighted different functions of sortilin in the immune system, notably in microglia, pro-inflammatory cytokine regulation, phagosome fusion and pathogen clearance. In this review, we will analyze the multiple roles of sortilin and SorLA in the human immune system and how their deregulation may be involved in disease development.

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Section: Sortilin Sorla and Inflammationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

et al. 2019

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“…Sortilin (Sort1, neurotensin receptor-3) is a type I transmembrane endocytosis receptor that has a multifunctional role in protein sorting and cell signaling 3 , 4 in a diverse range of cell types such as neurons, hepatocytes and white blood cells 5 . Sortilin can trigger internalization of ligands from the cell surface via endocytosis and sorts ligands between several intracellular compartments, such as the trans-Golgi network (TGN), endosomes, lysosomes, and the secretory pathway 6 – 8 .…”

Section: Introductionmentioning

confidence: 99%

Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release

et al. 2017

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Low pH-induced ligand release and receptor recycling are important steps for endocytosis. The transmembrane protein sortilin, a β-propeller containing endocytosis receptor, internalizes a diverse set of ligands with roles in cell differentiation and homeostasis. The molecular mechanisms of pH-mediated ligand release and sortilin recycling are unresolved. Here we present crystal structures that show the sortilin luminal segment (s-sortilin) undergoes a conformational change and dimerizes at low pH. The conformational change, within all three sortilin luminal domains, provides an altered surface and the dimers sterically shield a large interface while bringing the two s-sortilin C-termini into close proximity. Biophysical and cell-based assays show that members of two different ligand families, (pro)neurotrophins and neurotensin, preferentially bind the sortilin monomer. This indicates that sortilin dimerization and conformational change discharges ligands and triggers recycling. More generally, this work may reveal a double mechanism for low pH-induced ligand release by endocytosis receptors.

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“…APP (amyloid precursor protein) processing is modulated by SorCS1 [13]. It's well known that SorCS1 is expressed in pancreatic islet cells and its expression is associated with glucose homeostasis and insulin secretion [21]. Although little is known about SorCS1 in cancers, some SorCS1 related genes, such as PDGF-BB, STAT3 and synaptic proteins Neurexin and AMPARs [22,23] had been shown to be correlated with cancer development in many studies [24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of SorCS1 in colorectal cancer: An independent predictor of poor prognosis

Huang

Peng

et al. 2020

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Previously, we identified that sortilin related VPS10 domain containing receptor 1 (SorCS1) was hypermethylated in colorectal cancer (CRC) tissues. Here, we aimed to investigate the association between CRC and SorCS1. DNA methylation was determined by methylation-specific polymerase chain reaction (MSP) or quantitative real-time methylation analysis (MethyLight). Colorectal cancer tissue specimens from 239 patients that had undergone surgical treatment were evaluated using immunohistochemistry (IHC) analysis for the expression of SorCS1 and correlated with clinicopathological variables and prognosis. We found that SorCS1 was hypermethylated in CRC cell lines and 67.5% (27/40) CRC tumor tissues. The loss of SorCS1 mRNA (p<0.001) and protein expression (p=0.033) were highly correlated with promoter methylation. In addition, SorCS1 expression was significantly increased in younger patients (p=0.006), low CEA level (p<0.001) and pT1-2 stage (p=0.005). Survival analysis revealed that decreased expression of SorCS1 was an independent factor for predicting the increased risk of recurrence (p=0.024) and poor overall survival (p=0.006). Subgroup analysis for CEA level, pT and pN classifications showed that SorCS1 retained its stratified significance only in patients with low CEA level, pT3-4 tumors and pN1-2 lymph node status. Our findings suggest that SorCS1 is epigenetically inactivated in a substantial fraction of CRC, and its expression may be a promising prognostic factor in CRC patients.

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Protein sorting gone wrong – VPS10P domain receptors in cardiovascular and metabolic diseases

Cited by 30 publications

References 77 publications

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

Regulatory Roles of Sortilin and SorLA in Immune-Related Processes

Low pH-induced conformational change and dimerization of sortilin triggers endocytosed ligand release

Decreased expression of SorCS1 in colorectal cancer: An independent predictor of poor prognosis

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