PUBLICATION
Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling
- Authors
- Romano, D., Nguyen, L.K., Matallanas, D., Halasz, M., Doherty, C., Kholodenko, B.N., Kolch, W.
- ID
- ZDB-PUB-170214-323
- Date
- 2014
- Source
- Nature cell biology 16: 673-84 (Journal)
- Registered Authors
- Keywords
- Apoptosis, Cell signalling, Computer modelling, Growth factor signalling
- MeSH Terms
-
- Animals
- Apoptosis/physiology
- Cell Proliferation
- Cells, Cultured
- Embryo, Nonmammalian
- Genes, Switch/physiology*
- HEK293 Cells
- HeLa Cells
- Humans
- MAP Kinase Signaling System/physiology
- MCF-7 Cells
- Mice
- Models, Biological*
- NIH 3T3 Cells
- Phosphorylation
- Protein Binding
- Protein Serine-Threonine Kinases/metabolism*
- Proto-Oncogene Proteins c-raf/metabolism*
- Signal Transduction*
- Zebrafish/embryology
- PubMed
- 24929361 Full text @ Nat. Cell Biol.
Citation
Romano, D., Nguyen, L.K., Matallanas, D., Halasz, M., Doherty, C., Kholodenko, B.N., Kolch, W. (2014) Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling. Nature cell biology. 16:673-84.
Abstract
Signal transduction requires the coordination of activities between different pathways. In mammalian cells, Raf-1 regulates the MST-LATS and MEK-ERK pathways. We found that a complex circuitry of competing protein interactions coordinates the crosstalk between the ERK and MST pathways. Combining mathematical modelling and experimental validation we show that competing protein interactions can cause steep signalling switches through phosphorylation-induced changes in binding affinities. These include Akt phosphorylation of MST2 and a feedback phosphorylation of Raf-1 Ser 259 by LATS1, which enables Raf-1 to suppress both MST2 and MEK signalling. Mutation of Raf-1 Ser 259 stimulates both pathways, simultaneously driving apoptosis and proliferation, whereas concomitant MST2 downregulation switches signalling to cell proliferation, transformation and survival. Thus, competing protein interactions provide a versatile regulatory mechanism for signal distribution through the dynamic integration of graded signals into switch-like responses.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping