Alternative titles; symbolsLARGE TUMOR SUPPRESSOR, DROSOPHILA, HOMOLOG OF, 2HGNC Approved Gene Symbol: LATS2Cytogenetic location: 13q12.11 Genomic coordinate...
Alternative titles; symbols
HGNC Approved Gene Symbol: LATS2
Cytogenetic location: 13q12.11 Genomic coordinates (GRCh38): 13:20,973,035-21,061,585 (from NCBI)
▼ Cloning and Expression
The Drosophila 'large tumor suppressor' (lats) gene encodes a putative serine/threonine kinase (see LATS1, 603473). By screening a human testis cDNA library with a mouse Lats2 cDNA, Yabuta et al. (2000) isolated a partial human LATS2 cDNA. The human LATS2 cDNA encodes a deduced 1,046-amino acid partial protein lacking N-terminal sequence. LATS2 contains a PAPA repeat consisting of 7 copies of the dipeptide proline-alanine, which may be involved in protein-protein interactions, and a C-terminal serine/threonine kinase domain. Analysis of the amino acid sequences of the human and mouse LATS2 kinase domains indicated that the LATS2 proteins are most closely related to the LATS1 proteins, followed by Drosophila Lats, among known serine/threonine kinases. Immunoblot analysis of human cell lines showed that endogenous LATS2 is a nuclear protein of approximately 125 kD. Northern blot analysis detected a 5.8-kb LATS2 transcript in several human tissues, with highest expression in heart and skeletal muscle. Testis also expressed a 3.8-kb LATS2 transcript, which the authors suggested had a shorter 3-prime untranslated region than the 5.8-kb LATS2 transcript.
▼ Gene Function
Damage to the mitotic spindle and centrosome dysfunction trigger a succession of checkpoint responses that lead to tetraploid G1 cells that undergo a p53 (191170)-dependent G1/S arrest. Aylon et al. (2006) reported that LATS2 interacted physically with MDM2 (164785) to inhibit p53 ubiquitination and to promote p53 activation. The interaction was enhanced in mammalian cells treated with nocodazole, which provokes centrosome/mitotic apparatus dysfunction. Nocodazole caused LATS2 translocation from the centrosome into the nucleus, followed by p53 activation. A moderate excess of wildtype but not kinase-dead LATS2 potentiated p53-dependent G1 arrest in nocodazole-treated cells, thereby preventing tetraploidization. In contrast, downregulation of LATS2 compromised the p53-mediated G1 tetraploidy checkpoint. The LATS2 gene was itself a target for positive transcriptional regulation by p53 following treatment with nocodazole. LATS2 expression was not affected by other cell stresses that trigger G1/S or G2/M checkpoints. Aylon et al. (2006) concluded that the LATS2-MDM2-p53 axis constitutes a positive feedback checkpoint pathway critical for the maintenance of proper chromosome number following mitotic apparatus dysfunction.
Dgcr8 (609030)-knockout mouse embryonic stem (ES) cells lack microRNAs (miRNAs), proliferate slowly, and accumulate in G1 phase of the cell cycle. By screening mouse miRNAs for those that could rescue the growth defect in Dgcr8-knockout mouse ES cells, Wang et al. (2008) identified a group of related ES cell-specific miRNAs, including several members of the miR290 cluster. Target sites for these miRNAs were identified in the 3-prime UTRs of several inhibitors of the cyclin E (see CCNE1; 123837)-CDK2 (116953) pathway, including Cdkn1a (116899), Rb1 (614041), Rbl1 (116957), Rbl2 (180203), and Lats2 (604861). Quantitative RT-PCR confirmed increased expression of these genes in Dgcr8-knockout mouse ES cells.
Britschgi et al. (2017) used a high-content confocal image-based short hairpin RNA screen to identify tumor suppressors that regulate breast cell fate in primary human breast epithelial cells and showed that ablation of the large tumor suppressor kinases LATS1 and LATS2, which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells of origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and estrogen receptor-alpha (ESRA; 133430) signaling. In the presence of LATS, ESRA was targeted for ubiquitination and DDB1-CUL4-associated-factor 1 (DCAF1; 617259)-dependent proteasomal degradation. Absence of LATS stabilized ESRA and the Hippo effectors YAP (606608) and TAZ (607392), which together control breast cell fate through intrinsic and paracrine mechanisms. Britschgi et al. (2017) concluded that their findings revealed a noncanonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.
By FISH, Yabuta et al. (2000) mapped the human LATS2 gene to 13q11-q12. They mapped the mouse Lats2 gene to the central region of chromosome 14.
▼ Animal Model
McPherson et al. (2004) found that Lats2 deletion in mice was lethal between embryonic days 10.5 and 12.5. Mutant embryos were typically smaller or developmentally delayed and occasionally were found to contain distended blood-filled pericardia, hemorrhaging in the body or head region, and irregular kinked neural tubes. Disruption of Lats2 exerted contrasting roles in proliferation depending on the cellular context. Although Lats2 -/- embryos exhibited an arrest in proliferation prior to embryonic lethality, Lats2 -/- mouse embryonic fibroblasts acquired a growth advantage. Mutant embryonic cells exhibited an increased frequency of cytokinesis defects, micronuclei accumulation, supernumerary centrosomes, and aneuploidy. McPherson et al. (2004) concluded that LATS2 has a role in the maintenance of mitotic fidelity and genomic integrity.