Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions
| Autor: | Farida Latif, Adrianna Henson, Nadia P.C. Allen, Thomas L. Dunwell, Howard Donninger, Laura E. Gordon, Geoffrey J. Clark, Andrew Williams, Jennifer Pogue, Susannah Kassler |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
endocrine system
Apoptosis Cell Cycle Proteins Protein Serine-Threonine Kinases Biology Biochemistry Mice Cell Line Tumor Animals Humans Tumor Protein p73 Phosphorylation Molecular Biology Transcription factor Hippo signaling pathway Kinase Effector Tumor Suppressor Proteins Cell Cycle fungi Nuclear Proteins Signal transducing adaptor protein Cell Biology Cell biology DNA-Binding Proteins body regions Drosophila melanogaster HEK293 Cells Signal transduction Protein Binding Signal Transduction Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 286:18483-18491 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110.214874 |
| Popis: | The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects. However, although serving as an adaptor for MST and LATS, Salvador can also bind RASSF1A. The functional role of the RASSF1A/Salvador interaction is unclear. Although Salvador is a novel tumor suppressor in Drosophila and mice, its role in human systems remains largely unknown. Here we show that Salvador promotes apoptosis in human cells and that Salvador inactivation deregulates the cell cycle and enhances the transformed phenotype. Moreover, we show that although the salvador gene is seldom mutated or epigenetically inactivated in human cancers, it is frequently down-regulated posttranscriptionally. Surprisingly, we also find that although RASSF1A requires the presence of Salvador for full apoptotic activity and to activate p73, this effect does not require a direct interaction of RASSF1A with MST kinases or the activation of the hippo pathway. Thus, we confirm a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|