title: The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila.
abstract: Similar to the mammalian intestine, the Drosophila adult midgut has resident stem cells that support growth and regeneration. How the niche regulates intestinal stem cell activity in both mammals and flies is not well understood. Here, we show that the conserved germinal center protein kinase Misshapen restricts intestinal stem cell division by repressing the expression of the JAK-STAT pathway ligand Upd3 in differentiating enteroblasts. Misshapen, a distant relative to the prototypic Warts activating kinase Hippo, interacts with and activates Warts to negatively regulate the activity of Yorkie and the expression of Upd3. The mammalian Misshapen homolog MAP4K4 similarly interacts with LATS (Warts homolog) and promotes inhibition of YAP (Yorkie homolog). Together, this work reveals that the Misshapen-Warts-Yorkie pathway acts in enteroblasts to control niche signaling to intestinal stem cells. These findings also provide a model in which to study requirements for MAP4K4-related kinases in MST1/2-independent regulation of LATS and YAP.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shuangxi
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mana-Capelli
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Danai
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Alla
authors.initials: A
authors.lastname: Amcheslavsky
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Nie
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Xiaohao
authors.initials: X
authors.lastname: Yao
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Xiaochu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cotton
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Dannel
authors.initials: D
authors.lastname: McCollum
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: lxu@blueprintmedicines.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: tony.ip@umassmed.edu.
authors.forename: Y Tony
authors.initials: YT
authors.lastname: Ip
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D029721:Drosophila Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; D011494:Protein Kinases; C113875:msn protein, Drosophila; C093503:wts protein, Drosophila; D017346:Protein Serine-Threonine Kinases