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Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity

Nature Genetics volume 21, pages 177–181 (1999)Cite this article

Abstract

We have previously used mosaic flies to screen for tumour suppressors or negative regulators of cell proliferation1. The cellular composition of these flies resembles that of cancer patients who are chimaeric individuals carrying a small number of mutated somatic cells. One of the genes we identified is the large tumour suppressor gene, lats (also known as wts), which encodes a putative serine/threonine kinase1,2. Somatic cells mutant for lats undergo extensive proliferation and form large tumours in many tissues in mosaic adults. Homozygous mutants for various lats alleles display a range of developmental defects including embryonic lethality1. Although many tumour suppressors have been identified in Drosophila melanogaster3,4,5,6,7, it is not clear whether these fly genes are directly relevant to tumorigenesis in mammals. Here, we have isolated mammalian homologues of Drosophila lats. Human LATS1 suppresses tumour growth and rescues all developmental defects, including embryonic lethality in flies. In mammalian cells, LATS1 is phosphorylated in a cell–cycle–dependent manner and complexes with CDC2 in early mitosis. LATS1–associated CDC2 has no mitotic cyclin partner and no kinase activity for histone H1. Furthermore, lats mutant cells in Drosophila abnormally accumulate cyclin A. These biochemical observations indicate that LATS is a novel negative regulator of CDC2/cyclin A, a finding supported by genetic data in Drosophila demonstrating that lats specifically interacts with cdc2 and cyclin A.

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Figure 1: Human LATS1 and related proteins.
Figure 2: Human LATS1 can functionally replace Drosophila lats.
Figure 3: Phosphorylation of LATS1 and its association with CDC2 oscillate with the cell cycle.
Figure 4: Genetic interaction between lats and cdc2 in Drosophila .

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Acknowledgements

We thank H. Zhang for advice; T. Grigliatti and C. Lehner for reagents; members of the Xu lab for comments; and W. Yu, T. Ding, X. Fei and K. Sepanek for assistance. W.T. was an Anna Fuller fellow. G.S.T. is an NSF graduate fellow. S.Z. and R.S. are YUF students. M.S.J. is a MSTP student. This work is supported in part by grants from NIH (R01CA69408) and the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

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  1. Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536–0812, Connecticut, USA

    Wufan Tao, Sheng Zhang, Gregory S Turenchalk, Weili Chen & Tian Xu

  2. Department of Biology, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536–0812, Connecticut, USA

    Rodney A Stewart

  3. Department of Cell Biology, Howard Hughes Medical Institute, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, 06536–0812, Connecticut , USA

    Maie A R St John

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Correspondence to Tian Xu.

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Tao, W., Zhang, S., Turenchalk, G. et al. Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. Nat Genet 21, 177–181 (1999). https://doi.org/10.1038/5960

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