TGF-β Targets the Hippo Pathway Scaffold RASSF1A to Facilitate YAP/SMAD2 Nuclear Translocation.
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.
CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
Dafni-Eleftheria
DE
Pefani
CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
Daniela
D
Pankova
CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
Aswin G
AG
Abraham
CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
Anna M
AM
Grawenda
CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
Nikola
N
Vlahov
CRUK/MRC Institute for Radiation Oncology and Department of Oncology, University of Oxford, Oxford OX3 7DQ UK.
Simon
S
Scrace
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.
Eric
E
O' Neill
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D000090683:Hippo Signaling Pathway; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C411762:RASSF1 protein, human; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C508960:TGFB1 protein, human; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I