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

Dafni-Eleftheria Pefani; Daniela Pankova; Aswin G Abraham; Anna M Grawenda; Nikola Vlahov; Simon Scrace; Eric O' Neill

doi:10.1016/j.molcel.2016.05.012

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.

Authors

Dafni-Eleftheria Pefani¹, Daniela Pankova¹, Aswin G Abraham¹, Anna M Grawenda¹, Nikola Vlahov¹, Simon Scrace¹, Eric O' Neill²

Affiliations

¹ CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
² CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK. Electronic address: eric.oneill@oncology.ox.ac.uk.

PMID: 27292796
DOI: 10.1016/j.molcel.2016.05.012

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
Hippo Signaling Pathway
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
YAP-Signaling Proteins

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
YAP-Signaling Proteins
YAP1 protein, human
ITCH protein, human
Ubiquitin-Protein Ligases
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I

Abstract

MeSH terms

Substances

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