Lats2, a putative tumor suppressor, inhibits G1/S transition

Abstract

Lats2 is a new member of the Lats tumor suppressor family. The human LATS2 gene is located at chromosome 13q11-12, which has been shown to be a hot spot (67%) for LOH in nonsmall cell lung cancer. In order to understand the function of LATS2 in the control of tumor development, we ectopically expressed mouse Lats2 via retroviral infection in NIH3T3/v-ras cells to examine whether Lats2 plays a role in suppressing tumor development and regulating cell proliferation. We have found that ectopic expression of Lats2 in NIH3T3/v-ras cells suppresses development of tumors in athymic nude mice and inhibits proliferation of NIH3T3/v-ras cells in an in vitro assay. Cell cycle profile analysis demonstrated that ectopic expression of Lats2 inhibited the G1/S transition. Further mechanistic studies revealed that cyclin E/CDK2 kinase activity was downregulated in Lats2-transduced NIH3T3/v-ras cells, while other cell cycle regulators controlling the G1/S transition were not affected. We have also shown that LATS2 kinase activity and two LATS conserved domains (LCDs) are required for Lats2 to suppress tumorigenicity and to inhibit cell growth. In addition, the LATS2 protein is cytoplasmic during interphase in NIH3T3 cells, while it becomes localized to the mitotic apparatus during mitosis. Finally, we propose a model in which a combination of mammalian Lats2 and Lats1 control cell proliferation by negatively regulating different cell cycle check points.

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

“…In contrast, LATS2 (the second human counterpart of Drosophila Lats) seems to function in more than one cell cycle stage. On one hand, it was reported that LATS2 overexpression inhibits G1/S transition [90]. On the other hand, LATS2 overexpression can also lead to a G2/M cell cycle arrest [91].…”

Molecular characterization of human homologs of yeast MOB1

“…Over-expression of LATS1 also up-regulates the proapoptotic protein BAX in human mammary tumor cells and the activity of caspase-3 in human colorectal tumor cells to induce apoptosis [24,25]. Meanwhile, LATS2 has been demonstrated to regulate cell growth by inducing cell cycle arrest at the G 1 /S phase through the disruption of the CDK2/Cyclin E complex or at the G 2 /M phase by inhibiting Cdc2 kinase activity, by an as yet unknown mechanism [27,28]. Moreover, LATS2-deficient MEFs (Mouse Embryonic Fibroblasts) exhibit defects in growth control and centrosome duplication, which results in misalignment of chromosomes and failure of cytokinesis [23].…”

“…The LATS/NDR protein kinase family has been implicated in many cellular processes and LATS1/2 has been shown to suppress tumor growth [23,24,25,27,30,32]. …”

The Hippo in the room: A new look at a key pathway in cell growth and transformation

“…34 Beside their roles within the Hippo pathway, Lats1/2 may regulate cell cycle progression and apoptosis. [35][36][37][38] Lats1 has been shown to regulate both mitotic exit 39 and cytokinesis 40 and to play a role in cellular senescence, since reduction of Lats1 levels is, at least partly, responsible for cytokinetic block in senescent cells. 41 Lats2 has also been found to protect p53 from Mdm2-mediated degradation while p53 stimulates Lats2 expression.…”

“…49 In vitro, overexpression of Lats1 or Lats2 is sufficient to suppress ephithelial-messenchymal transition and tumor growth of cancer cells while their downregulation result in cell overgrowth and transformation. 32,35,36,44,45,50 …”