title: Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling.
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.
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Romano
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Matallanas
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Melinda
authors.initials: M
authors.lastname: Halasz
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Carolanne
authors.initials: C
authors.lastname: Doherty
authors.affiliation: 1] Systems Biology Ireland, University College Dublin, Dublin 4, Ireland [2] Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland [3] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland [4].
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: 1] Systems Biology Ireland, University College Dublin, Dublin 4, Ireland [2] Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland [3] School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland [4].
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian; D005812:Genes, Switch / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D061986:MCF-7 Cells; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology; D000099317:Hippo Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D000090742:Serine-Threonine Kinase 3; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases