Opposing activities of the Ras and Hippo pathways converge on regulation of YAP protein turnover
| Autor: | P. Mathijs Voorhoeve, Qingfeng Chen, Rui Zhang, Hung Thanh Nguyen, Xin Hong, Stephen M. Cohen, Zandra Hagman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Beta-Transducin Repeat-Containing Proteins
tumor suppressor Hippo pathway Biology Protein Serine-Threonine Kinases medicine.disease_cause General Biochemistry Genetics and Molecular Biology Downregulation and upregulation Amphiregulin medicine Humans Hippo Signaling Pathway Molecular Biology Adaptor Proteins Signal Transducing YAP1 Hippo signaling pathway General Immunology and Microbiology General Neuroscience YAP-Signaling Proteins Articles Phosphoproteins RasV12 primary cell transformation Cell biology Cell Transformation Neoplastic Ubiquitin ligase complex anchorage independence ras Proteins Signal transduction Carcinogenesis Signal Transduction Transcription Factors |
| Zdroj: | The EMBO Journal |
| ISSN: | 1460-2075 0261-4189 |
| Popis: | Cancer genomes accumulate numerous genetic and epigenetic modifications. Yet, human cellular transformation can be accomplished by a few genetically defined elements. These elements activate key pathways required to support replicative immortality and anchorage independent growth, a predictor of tumorigenesis in vivo. Here, we provide evidence that the Hippo tumor suppressor pathway is a key barrier to Ras-mediated cellular transformation. The Hippo pathway targets YAP1 for degradation via the βTrCP-SCF ubiquitin ligase complex. In contrast, the Ras pathway acts oppositely, to promote YAP1 stability through downregulation of the ubiquitin ligase complex substrate recognition factors SOCS5/6. Depletion of SOCS5/6 or upregulation of YAP1 can bypass the requirement for oncogenic Ras in anchorage independent growth in vitro and tumor formation in vivo. Through the YAP1 target, Amphiregulin, Ras activates the endogenous EGFR pathway, which is required for transformation. Thus, the oncogenic activity of RasV12 depends on its ability to counteract Hippo pathway activity, creating a positive feedback loop, which depends on stabilization of YAP1. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text