Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity

EMBO J. 2004 Sep 15;23(18):3677-88. doi: 10.1038/sj.emboj.7600371. Epub 2004 Sep 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Lineage
  • Cell Proliferation*
  • Centrosome / physiology
  • Cytokinesis
  • Female
  • Fibroblasts / physiology
  • Gene Amplification
  • Genes, Lethal
  • Genomic Instability*
  • Male
  • Mesoderm / metabolism
  • Mice / embryology*
  • Mice, Inbred C57BL
  • Mitosis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Spindle Apparatus
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • Tumor Suppressor Proteins
  • LATS1 protein, human
  • LATS2 protein, human
  • Protein-Serine-Threonine Kinases