CIN85 modulates TGFβ signaling by promoting the presentation of TGFβ receptors on the cell surface

J Cell Biol. 2015 Jul 20;210(2):319-32. doi: 10.1083/jcb.201411025. Epub 2015 Jul 13.

Abstract

Members of the transforming growth factor β (TGFβ) family initiate cellular responses by binding to TGFβ receptor type II (TβRII) and type I (TβRI) serine/threonine kinases, whereby Smad2 and Smad3 are phosphorylated and activated, promoting their association with Smad4. We report here that TβRI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGFβ stimulation in a TRAF6-dependent manner. Small interfering RNA-mediated knockdown of CIN85 resulted in accumulation of TβRI in intracellular compartments and diminished TGFβ-stimulated Smad2 phosphorylation. Overexpression of CIN85 instead increased the amount of TβRI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGFβ receptors. CIN85 enhanced TGFβ-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGFβ receptors and thereby positively regulates TGFβ signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Male
  • Molecular Sequence Data
  • Prostatic Neoplasms / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Transport
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / physiology*
  • rab GTP-Binding Proteins / genetics
  • rab GTP-Binding Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Receptors, Transforming Growth Factor beta
  • SH3KBP1 protein, human
  • TNF Receptor-Associated Factor 6
  • Transforming Growth Factor beta
  • rab11 protein
  • rab GTP-Binding Proteins

Associated data

  • RefSeq/NM_031892
  • SWISSPROT/P20338
  • SWISSPROT/P36897
  • SWISSPROT/P37173
  • SWISSPROT/P62491
  • SWISSPROT/P70196
  • SWISSPROT/Q96B97