Sortilin associates with transforming growth factor-β family proteins to enhance lysosome-mediated degradation

Sunjong Kwon, Jan L. Christian

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)21876-21885
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number24
DOIs
StatePublished - Jun 17 2011

Fingerprint

Transforming Growth Factors
Lysosomes
Degradation
Protein Precursors
Proteins
Ligands
Biosynthetic Pathways
Protein Transport
Xenopus
HeLa Cells
sortilin
Bone
Up-Regulation
Down-Regulation
Embryonic Structures
Chemical activation
Bone and Bones

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Sortilin associates with transforming growth factor-β family proteins to enhance lysosome-mediated degradation. / Kwon, Sunjong; Christian, Jan L.

In: Journal of Biological Chemistry, Vol. 286, No. 24, 17.06.2011, p. 21876-21885.

Research output: Contribution to journalArticle

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