title: Sortilin associates with transforming growth factor-beta family proteins to enhance lysosome-mediated degradation.
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.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239, USA.
authors.forename: Sunjong
authors.initials: S
authors.lastname: Kwon
authors.forename: Jan L
authors.initials: JL
authors.lastname: Christian
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D018076:DNA, Complementary / Q000378:metabolism; D004705:Endocytosis; D018507:Gene Expression Regulation, Developmental; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014982:Xenopus laevis; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019485:Bone Morphogenetic Proteins; D018076:DNA, Complementary; D016212:Transforming Growth Factor beta; D000099183:Sortilin