Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling

David Romano, Lan K Nguyen, David Matallanas, Melinda Halasz, Carolanne Doherty, Boris Kholodenko, Walter Kolch

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94 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)673-684
Number of pages12
JournalNature Cell Biology
Issue number7
Publication statusPublished - 15 Jun 2014
Externally publishedYes

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