TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation

Mol Cell. 2016 Jul 7;63(1):156-66. doi: 10.1016/j.molcel.2016.05.012. Epub 2016 Jun 9.

Abstract

Epigenetic inactivation of the Hippo pathway scaffold RASSF1A is associated with poor prognosis in a wide range of sporadic human cancers. Loss of expression reduces tumor suppressor activity and promotes genomic instability, but how this pleiotropic biomarker is regulated at the protein level is unknown. Here we show that TGF-β is the physiological signal that stimulates RASSF1A degradation by the ubiquitin-proteasome pathway. In response to TGF-β, RASSF1A is recruited to TGF-β receptor I and targeted for degradation by the co-recruited E3 ubiquitin ligase ITCH. RASSF1A degradation is necessary to permit Hippo pathway effector YAP1 association with SMADs and subsequent nuclear translocation of receptor-activated SMAD2. We find that RASSF1A expression regulates TGF-β-induced YAP1/SMAD2 interaction and leads to SMAD2 cytoplasmic retention and inefficient transcription of TGF-β targets genes. Moreover, RASSF1A limits TGF-β induced invasion, offering a new framework on how RASSF1A affects YAP1 transcriptional output and elicits its tumor-suppressive function.

MeSH terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Movement
  • DNA Methylation
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Neoplasm Invasiveness
  • Phosphoproteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteolysis
  • RNA Interference
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Smad2 Protein / metabolism*
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Transforming Growth Factor beta1 / metabolism*
  • Transforming Growth Factor beta1 / pharmacology
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • RASSF1 protein, human
  • Receptors, Transforming Growth Factor beta
  • Repressor Proteins
  • SMAD2 protein, human
  • Smad2 Protein
  • TGFB1 protein, human
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Tumor Suppressor Proteins
  • YAP1 (Yes-associated) protein, human
  • ITCH protein, human
  • Ubiquitin-Protein Ligases
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I