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 un...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2016
|
| _version_ | 1797070846443913216 |
|---|---|
| author | Pefani, E Pankova, D Abraham, A Grawenda, A Vlahov, N Scrace, S O'Neill, E |
| author_facet | Pefani, E Pankova, D Abraham, A Grawenda, A Vlahov, N Scrace, S O'Neill, E |
| author_sort | Pefani, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:44:51Z |
| format | Journal article |
| id | oxford-uuid:5cd1c127-1457-4f4d-92bb-a3b3f9c615ff |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:44:51Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:5cd1c127-1457-4f4d-92bb-a3b3f9c615ff2022-03-26T17:30:28ZTGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5cd1c127-1457-4f4d-92bb-a3b3f9c615ffEnglishSymplectic Elements at OxfordElsevier2016Pefani, EPankova, DAbraham, AGrawenda, AVlahov, NScrace, SO'Neill, EEpigenetic 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. |
| spellingShingle | Pefani, E Pankova, D Abraham, A Grawenda, A Vlahov, N Scrace, S O'Neill, E TGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation |
| title | TGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation |
| title_full | TGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation |
| title_fullStr | TGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation |
| title_full_unstemmed | TGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation |
| title_short | TGF-β targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation |
| title_sort | tgf β targets the hippo pathway scaffold rassf1a to facilitate yap smad2 nuclear translocation |
| work_keys_str_mv | AT pefanie tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation AT pankovad tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation AT abrahama tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation AT grawendaa tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation AT vlahovn tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation AT scraces tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation AT oneille tgfbtargetsthehippopathwayscaffoldrassf1atofacilitateyapsmad2nucleartranslocation |