title: ABL1 regulates spindle orientation in adherent cells and mammalian skin.
abstract: Despite the growing evidence for the regulated spindle orientation in mammals, a systematic approach for identifying the responsible genes in mammalian cells has not been established. Here we perform a kinase-targeting RNAi screen in HeLa cells and identify ABL1 as a novel regulator of spindle orientation. Knockdown of ABL1 causes the cortical accumulation of Leu-Gly-Asn repeat-enriched-protein (LGN), an evolutionarily conserved regulator of spindle orientation. This results in the LGN-dependent spindle rotation and spindle misorientation. In vivo inactivation of ABL1 by a pharmacological inhibitor or by ablation of the abl1 gene causes spindle misorientation and LGN mislocalization in mouse epidermis. Furthermore, ABL1 directly phosphorylates NuMA, a binding partner of LGN, on tyrosine 1774. This phosphorylation maintains the cortical localization of NuMA during metaphase, and ensures the LGN/NuMA-dependent spindle orientation control. This study provides a novel approach to identify genes regulating spindle orientation in mammals and uncovers new signalling pathways for this mechanism.
authors.affiliation: Department of Cell Biology, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsumura
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hamasaki
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Miki
authors.initials: M
authors.lastname: Ebisuya
authors.forename: Mizuho
authors.initials: M
authors.lastname: Sato
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
authors.forename: Fumiko
authors.initials: F
authors.lastname: Toyoshima
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D008941:Spindle Apparatus; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry
chemical_list: D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl