title: MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.
abstract: The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Moroishi
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of Disease and Katholieke Universiteit Leuven Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Violaine
authors.initials: V
authors.lastname: Mottier-Pavie
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Plouffe
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Hansen
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Audrey W
authors.initials: AW
authors.lastname: Hong
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Shicong
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Flores
authors.affiliation: Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of Disease and Katholieke Universiteit Leuven Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Georg
authors.initials: G
authors.lastname: Halder
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D000217:Acyltransferases; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004330:Drosophila; D029721:Drosophila Proteins; D005455:Fluorescent Antibody Technique; D000081410:Germinal Center Kinases; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D000217:Acyltransferases; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D000081410:Germinal Center Kinases; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C456659:YY1AP1 protein, human; C082332:macrophage stimulating protein; C108675:TAFAZZIN protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; C117090:MAP4K4 protein, human; C102102:hematopoietic progenitor kinase 1; C543044:MAP4K3 protein, human; C497353:MINK1 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases; C499474:hpo protein, Drosophila