Mst2 and Lats Kinases Regulate Apoptotic Function of Yes Kinase-associated Protein (YAP)
| Autor: | Marius Sudol, Virginia Mazack, Tsutomu Oka |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Cytoplasm
Amino Acid Motifs Apoptosis Cell Cycle Proteins Protein Serine-Threonine Kinases Biology Serine-Threonine Kinase 3 Biochemistry Mice Animals Drosophila Proteins Humans Tumor Protein p73 Phosphorylation Molecular Biology Transcription factor Adaptor Proteins Signal Transducing Cell Nucleus Hippo signaling pathway Kinase Tumor Suppressor Proteins HEK 293 cells Intracellular Signaling Peptides and Proteins Nuclear Proteins Signal transducing adaptor protein Epithelial Cells YAP-Signaling Proteins Organ Size Cell Biology Embryo Mammalian Phosphoproteins Protein Structure Tertiary Cell biology DNA-Binding Proteins Drosophila melanogaster NIH 3T3 Cells Signal Transduction Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 283:27534-27546 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m804380200 |
| Popis: | The Hippo pathway in Drosophila controls the size and shape of organs. In the fly, activation of this pathway conveys growth-inhibitory signals and promotes apoptosis in epithelial cells. We "reconstituted" the Hippo pathway in a human epithelial cell line and showed that, in contrast to flies, the activation of this pathway results in anti-apoptotic signals. We have shown that in human embryonic kidney (HEK) 293 cells, the complex formation between transcriptional co-activators YAPs (Yes kinase-associated proteins) and Lats kinases requires the intact WW domains of YAPs, as well as intact Pro-Pro-AA-Tyr (where AA is any amino acid) motifs in Lats kinases. These kinases cooperate with the upstream Mst2 kinase to phosphorylate YAPs at Ser-127. Overexpression of YAP2 in HEK293 cells promoted apoptosis, whereas the Mst2/Lats1-induced phosphorylation of YAP partially rescued the cells from apoptotic death. Apoptotic signaling of YAP2 was mediated via stabilization of p73, which formed a complex with YAP2. All components of the Hippo pathway that we studied were localized in the cytoplasm, with the exception of YAP, which also localized in the nucleus. The localization of YAP2 in the nucleus was negatively controlled by the Lats1 kinase. Our apoptotic "readout" of the Hippo pathway in embryonic kidney cells represents a useful experimental system for the identification of the putative upstream receptor, membrane protein, or extracellular factor that initiates an entire signaling cascade and ultimately controls the size of organs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|