title: Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity.
abstract: The Drosophila melanogaster warts/lats tumour suppressor has two mammalian counterparts LATS1/Warts-1 and LATS2/Kpm. Here, we show that mammalian Lats orthologues exhibit distinct expression profiles according to germ cell layer origin. Lats2(-/-) embryos show overgrowth in restricted tissues of mesodermal lineage; however, lethality ultimately ensues on or before embryonic day 12.5 preceded by defective proliferation. Lats2(-/-) mouse embryonic fibroblasts (MEFs) acquire growth advantages and display a profound defect in contact inhibition of growth, yet exhibit defective cytokinesis. Lats2(-/-) embryos and MEFs display centrosome amplification and genomic instability. Lats2 localizes to centrosomes and overexpression of Lats2 suppresses centrosome overduplication induced in wild-type MEFs and reverses centrosome amplification inherent in Lats2(-/-) MEFs. These findings indicate an essential role of Lats2 in the integrity of processes that govern centrosome duplication, maintenance of mitotic fidelity and genomic stability.
authors.affiliation: Division of Cellular & Molecular Biology, Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John Peter
authors.initials: JP
authors.lastname: McPherson
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.forename: Andrew
authors.initials: A
authors.lastname: Elia
authors.forename: Eva
authors.initials: E
authors.lastname: Migon
authors.forename: Amro
authors.initials: A
authors.lastname: Shehabeldin
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Matysiak-Zablocki
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Lemmers
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Anne
authors.initials: A
authors.lastname: Hakem
authors.forename: Jason
authors.initials: J
authors.lastname: Fish
authors.forename: Farah
authors.initials: F
authors.lastname: Kassam
authors.forename: Jeremy
authors.initials: J
authors.lastname: Squire
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.forename: M Prakash
authors.initials: MP
authors.lastname: Hande
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
mesh_terms: D000818:Animals; D017209:Apoptosis; D019070:Cell Lineage; D049109:Cell Proliferation; D018385:Centrosome / Q000502:physiology; D048749:Cytokinesis; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D005784:Gene Amplification; D005804:Genes, Lethal; D042822:Genomic Instability; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice / Q000196:embryology*; D008810:Mice, Inbred C57BL; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D008941:Spindle Apparatus; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D025521:Tumor Suppressor Proteins; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases