title: The hippo pathway core cassette regulates asymmetric cell division.
abstract: Asymmetric cell division (ACD) is a crucial process during development, homeostasis, and cancer. Stem and progenitor cells divide asymmetrically, giving rise to two daughter cells, one of which retains the parent cell self-renewal capacity, while the other is committed to differentiation. Any imbalance in this process can induce overgrowth or even a cancer-like state. Here, we show that core components of the Hippo signaling pathway, an evolutionarily conserved organ growth regulator, modulate ACD in Drosophila. Hippo pathway inactivation disrupts the asymmetric localization of ACD regulators, leading to aberrant mitotic spindle orientation and defects in the generation of unequal-sized daughter cells. The Hippo pathway downstream kinase Warts, LATS1-2 in mammals, associates with the ACD modulators Inscuteable and Bazooka in vivo and phosphorylates Canoe, the ortholog of Afadin/AF-6, in vitro. Moreover, phosphosite mutant Canoe protein fails to form apical crescents in dividing neuroblasts in vivo, and the lack of Canoe phosphorylation by Warts leads to failures of Discs Large apical localization in metaphase neuroblasts. Given the relevance of ACD in stem cells during tissue homeostasis, and the well-documented role of the Hippo pathway as a tumor suppressor, these results represent a potential route for perturbations in the Hippo signaling to induce tumorigenesis via aberrant stem cell divisions.
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Alyona
authors.initials: A
authors.lastname: Keder
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Rives-Quinto
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Birgit L
authors.initials: BL
authors.lastname: Aerne
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Franco
authors.affiliation: The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tapon
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Alicante, Spain. Electronic address: acarmena@umh.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Carmena
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D000099317:Hippo Kinases
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases