title: A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway.
abstract: The Hippo-YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo-YAP signalling cascade.
authors.affiliation: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Sun
authors.affiliation: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Lau
authors.affiliation: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Curtis
authors.affiliation: Center for Pediatric Polyposis, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Goldsmith
authors.affiliation: Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Fox
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Chongjuan
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Marsha
authors.initials: M
authors.lastname: Frazier
authors.affiliation: Wnt Signaling and Colorectal Cancer Group, The Beatson Institute for Cancer Research, Cancer Research UK, Glasgow G61 1BD, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: Samson
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] Genetics Division, Department of Medicine Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, Massachusetts 02115, USA.
authors.forename: Kwok-Kim
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Carla
authors.initials: C
authors.lastname: Kim
authors.affiliation: 1] Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D005820:Genetic Testing; D057809:HEK293 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D013379:Substrate Specificity; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C105547:MARK1 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases