Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
???displayArticle.abstract???
Transforming growth factor (TGF)-β family proteins are synthesized as precursors that are cleaved to generate an active ligand. Previous studies suggest that TGF-β activity can be controlled by lysosomal degradation of both precursor proteins and ligands, but how these soluble proteins are trafficked to the lysosome is incompletely understood. The current studies show that sortilin selectively co-immunoprecipitates with the cleaved prodomain and/or precursor form of TGF-β family members. Furthermore, sortilin co-localizes with, and enhances accumulation of a nodal family member in the Golgi. Co-expression of sortilin with TGF-β family members leads to decreased accumulation of precursor proteins and cleavage products and this is attenuated by lysosomal, but not proteosomal inhibitors. In Xenopus embryos, overexpression of sortilin leads to a decrease in phospho-Smad2 levels and phenocopies loss of nodal signaling. Conversely, down-regulation of sortilin expression in HeLa cells leads to an up-regulation of endogenous bone morphogenic protein pathway activation, as indicated by an increase in phospho-Smad1/5/8 levels. Our results suggest that sortilin negatively regulates TGF-β signaling by diverting trafficking of precursor proteins to the lysosome during transit through the biosynthetic pathway.
Andersen,
Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
2005, Pubmed
Andersen,
Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
2005,
Pubmed Blanchet,
Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation.
2008,
Pubmed Blanchet,
Cripto localizes Nodal at the limiting membrane of early endosomes.
2008,
Pubmed Bogan,
Biogenesis and regulation of insulin-responsive vesicles containing GLUT4.
2010,
Pubmed Boutilier,
Proneurotrophins require endocytosis and intracellular proteolysis to induce TrkA activation.
2008,
Pubmed Bronfman,
Ligand-induced internalization of the p75 neurotrophin receptor: a slow route to the signaling endosome.
2003,
Pubmed Chang,
Function of the two Xenopus smad4s in early frog development.
2006,
Pubmed
,
Xenbase Chen,
Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway.
2005,
Pubmed Chen,
Endocytic regulation of TGF-beta signaling.
2009,
Pubmed Constam,
Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases.
1999,
Pubmed Cui,
The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor.
2001,
Pubmed
,
Xenbase Degnin,
Cleavages within the prodomain direct intracellular trafficking and degradation of mature bone morphogenetic protein-4.
2004,
Pubmed
,
Xenbase Ebisawa,
Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation.
2001,
Pubmed Goldman,
Mutation of an upstream cleavage site in the BMP4 prodomain leads to tissue-specific loss of activity.
2006,
Pubmed
,
Xenbase Harland,
In situ hybridization: an improved whole-mount method for Xenopus embryos.
1991,
Pubmed
,
Xenbase Heasman,
Patterning the early Xenopus embryo.
2006,
Pubmed
,
Xenbase Hermey,
The Vps10p-domain receptor family.
2009,
Pubmed Horton,
Gene splicing by overlap extension: tailor-made genes using the polymerase chain reaction.
1990,
Pubmed Hu,
Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin.
2010,
Pubmed Jansen,
Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury.
2007,
Pubmed Kavsak,
Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation.
2000,
Pubmed
,
Xenbase Kelley,
A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling.
2009,
Pubmed Kim,
NRH2 is a trafficking switch to regulate sortilin localization and permit proneurotrophin-induced cell death.
2009,
Pubmed Kjolby,
Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export.
2010,
Pubmed Konrad,
Characterization of the murine IgG Fc receptor III and IIB gene promoters: a single two-nucleotide difference determines their inverse responsiveness to C5a.
2007,
Pubmed Lamark,
Autophagy: links with the proteasome.
2010,
Pubmed Lefrancois,
The lysosomal trafficking of sphingolipid activator proteins (SAPs) is mediated by sortilin.
2003,
Pubmed Le Good,
Nodal stability determines signaling range.
2005,
Pubmed Lennon,
The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression.
1996,
Pubmed Marcusson,
The sorting receptor for yeast vacuolar carboxypeptidase Y is encoded by the VPS10 gene.
1994,
Pubmed Moustakas,
The regulation of TGFbeta signal transduction.
2009,
Pubmed Munck Petersen,
Propeptide cleavage conditions sortilin/neurotensin receptor-3 for ligand binding.
1999,
Pubmed Nakayama,
Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning.
1998,
Pubmed
,
Xenbase Ni,
The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin and mannose 6-phosphate receptor.
2006,
Pubmed Nielsen,
The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein.
2001,
Pubmed Nykjaer,
Sortilin is essential for proNGF-induced neuronal cell death.
2004,
Pubmed Petersen,
Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography.
1997,
Pubmed Quistgaard,
Ligands bind to Sortilin in the tunnel of a ten-bladed beta-propeller domain.
2009,
Pubmed Schmidt,
SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1.
2007,
Pubmed Shi,
The luminal Vps10p domain of sortilin plays the predominant role in targeting to insulin-responsive Glut4-containing vesicles.
2007,
Pubmed Shi,
Sortilin is essential and sufficient for the formation of Glut4 storage vesicles in 3T3-L1 adipocytes.
2005,
Pubmed Spoelgen,
Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.
2006,
Pubmed Tian,
The pro-domain of the zebrafish Nodal-related protein Cyclops regulates its signaling activities.
2008,
Pubmed
,
Xenbase Vaegter,
Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling.
2011,
Pubmed Walsh,
Extracellular BMP-antagonist regulation in development and disease: tied up in knots.
2010,
Pubmed Willnow,
VPS10P-domain receptors - regulators of neuronal viability and function.
2008,
Pubmed Wolins,
Aggregation as a determinant of protein fate in post-Golgi compartments: role of the luminal domain of furin in lysosomal targeting.
1997,
Pubmed Zeng,
The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes.
2009,
Pubmed Zhang,
Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors.
2004,
Pubmed
