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

Abstract

We have previously used mosaic flies to screen for tumour suppressors or negative regulators of cell proliferation. 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 kinase. 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 lethality. Although many tumour suppressors have been identified in Drosophila melanogaster, 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.

Hippo signalling in the G2/M cell cycle phase: Lessons learned from the yeast MEN and SIN pathways

“…In contrast, LATS1/2 kinases, which can also signal downstream of MST1/2 [13,14,83], have been shown to play a role in later stages of mitosis. A decade ago, it was reported that LATS1 can inhibit CDK1 activity in mitosis, thereby influencing G2/M cell cycle progression [25,84]. Analysis of cells overexpressing LATS1 supported a role for LATS1 in mitosis, since LATS1 overexpression resulted in a G2/M cell cycle arrest [84][85][86].…”

“…The authors speculated that Lats might accelerate progression through G2/M, thereby shifting more cells into G1 [59]. In light of the finding that Lats can inhibit CDK1 during mitosis in human cells and flies [25], this interpretation might be correct. However, we currently cannot exclude the other possible interpretation of this finding, namely that loss of Lats function results in a G1 cell cycle arrest.…”

“…Loss of Hippo, Mats or Warts could be functionally compensated by their mammalian counterparts MST2, LATS1 and MOB1A, respectively [24][25][26], strongly suggesting that, similar to the MEN/SIN, Hippo signalling is very highly conserved from flies to humans. Over the past years a series of studies using human cells and transgenic mice established that the core components of mammalian Hippo signalling represent tumour suppressor proteins [27][28][29][30][31].…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…1B). It has been demonstrated that human YAP, Lats1, Mst2, and Mob1 can rescue the phenotypes of their corresponding Drosophila mutants in vivo (Tao et al, 1999;Wu et al, 2003;Huang et al, 2005;Lai et al, 2005), suggesting the functional conservation of these proteins. The core components Mst1/2 are known to be pro-apoptotic kinases that are activated by caspase cleavage under apoptotic stress (Graves et al, 1998).…”

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

“…A mammalian homolog of the Drosophila tumorsuppressor protein warts, known as WARTS (or large tumor-suppressor 1 (LATS1)), was identified (Nishiyama et al, 1999;Tao et al, 1999) and found to have functions similar to its activity in Drosophila: mice deficient in WARTS (WTS)/LATS1 develop malignant tumors . WTS encodes a serine-threonine kinase that shares a high degree of sequence homology with members of the myotonic dystrophy protein kinase (DMPK) family, many of which participate in mitotic events.…”