Disease relevance of LATS1

• We demonstrate here that transduction of the human breast cancer cell MCF-7 with recombinant LATS1 adenovirus (Ad-LATS1), but not with EGFP adenovirus (Ad-EGFP), inhibits in vitro cell proliferation [1].
• We also demonstrate that ectopic expression of LATS1 in MCF-7 cells and human lung cancer cell H460 up-regulates the level of BAX proteins and induces apoptosis [1].
• We further analyzed alterations of the h-warts/LATS1 in these seven sarcomas [2].
• The reproductive hormone defects of Lats1-/- mice are reminiscent of isolated LH-hypogonadotropic hypogonadism and corpus luteum insufficiency in humans [3].
• Lats1-/- animals exhibit a lack of mammary gland development, infertility and growth retardation [3].

High impact information on LATS1

• The tumor suppressors Merlin, expanded, hippo, salvador and mob as tumor suppressor also share multiple Fat pathway phenotypes but regulate Warts activity independently [4].
• One of the genes we identified is the large tumour suppressor gene, lats (also known as wts), which encodes a putative serine/threonine kinase [5].
• Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction [3].
• Furthermore, Lats1-/- mice develop soft-tissue sarcomas and ovarian stromal cell tumours and are highly sensitive to carcinogenic treatments [3].
• Sustained activation of ROS-PKCdelta signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis, in human senescent cells [6].

Chemical compound and disease context of LATS1

• LATS was measured with the double isotope technique in IgG serum concentrates of 23 patients with Graves' disease before treatment and of 18 patients during treatment with carbimazole and triiodothyronine [7].
• Serum thyroid-stimulating autoantibodies (LATS and LATS protector) and thyrotropin (TSH) concentrations were measured in the serum of 30 patients with hyperthyroidism living in Tasmania who developed their disease following correction of iodine deficiency by addition of iodate to the bread [8].
• Neonatal thyrotoxicosis: alterations in serum concentrations of LATS-protector, T4, T3, reverse T3, and 3,3'T2 [9].
• External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts [10].
• Two full-size transcripts with mol. wts. of 0.74 and 0.66 X 10(6) (2.2 kb and 2 kb, respectively) were synthesized by the virus-associated RNA-dependent RNA polymerase and resolved by denaturing polyacrylamide gel electrophoresis [11].

Biological context of LATS1

• Inactivation of LATS1 by antibody microinjection or RNA-mediated interference in cells, or gene knockout in mice, abrogates cytokinesis and increases the percentage of multinucleate cells [12].
• These findings suggest that h-warts/LATS1 and zyxin play a crucial role in controlling mitosis progression by forming a regulatory complex on mitotic apparatus [13].
• These observations suggest that LATS1 is a potent growth suppressor and, like other tumor suppressors, it suppresses growth by inducing cell cycle arrest or apoptosis [14].
• Deletion analysis revealed that regulation of Lats1 occurs through the C-terminal, catalytic domain [15].
• Finally, we show that LATS1 kinase activity is required for its ability to inhibit cell growth and induce apoptosis [1].

Anatomical context of LATS1

• A human homologue of the Drosophila warts tumor suppressor, h-warts/LATS1, is an evolutionarily conserved serine/threonine kinase and a dynamic component of the mitotic apparatus [13].
• Indeed, moderate overexpression of human LATS1 in cells exposed to microtubule poisons facilitated mitotic exit, and this activity required MOB1A [16].
• Therefore, we suggest a potential in vivo mechanism of LATS1 activation through rapid recruitment to the plasma membrane by hMOB1 followed by multi-site phosphorylation, thereby providing insight into the molecular regulation of the LATS tumour suppressor [17].
• 1. The h-warts protein has a serine/threonine kinase domain and is localized to centrosomes in interphase cells [18].
• Phosphoproteins of closely related mol. wts. were immunoprecipitated from RSV-transformed avian fibroblasts [19].

Associations of LATS1 with chemical compounds

• On the basis of the deduced amino acid sequences and compositions and the mol. wts. of their encoded glycoproteins, the genes, dlec1 and dlec2, are predicted to encode erythro- and leucoagglutinating phytohemagglutinins (PHA-E and PHA-L), respectively [20].
• Nitrate influx via the low-affinity transport system (LATS) was unaffected [21].
• The serum or IgG fraction from one of them, however, did not contain any significant LATS, LATS-protector, or human thyroid adenylate cyclase-stimulating activity and caused inhibition of adenylate cyclase stimulation by TSH [22].
• No difference could be found in the mean values of total thyroxine, thyroid 131-I uptake and thyroid weight of the group of LATS positive and LATS negative patients before treatment [7].
• After pretreatment with 2-mercaptoethanol and sodium dodecyl sulphate, alpha-D-mannosidase dissociated into subunits of mol. wts. of 58 000 +/- 600 and 30 000 +/- 380 respectively [23].

Regulatory relationships of LATS1

• The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1 [15].
• We have discovered that LATS1 inactivates YAP oncogenic function by suppressing its transcription regulation of cellular genes via sequestration of YAP in the cytoplasm after phosphorylation of YAP [24].

Other interactions of LATS1

• Furthermore, the decreased expression of LATS1 mRNA, but not LATS2 mRNA, was significantly (P < 0.05) associated with a poor prognosis [25].
• In mammalians, the LATS kinase is a tumor suppressor, negatively regulating the cyclin-dependent kinase CDK1, cell proliferation rate, and modulating cell survival [26].
• Several chromosomal breakpoints flanking ESR1 affecting the region harboring LATS1 were found [27].
• This locus contains two major candidate tumor suppressor genes, PLAGL1 and LATS1 [28].

Analytical, diagnostic and therapeutic context of LATS1

• RESULTS: Methylation-specific PCR showed that of 30 tumors, LATS1 promoter region was hypermethylated in 17 tumors (56.7%) and LATS2 promoter region was hypermethylated in 15 (50.0%) tumors [25].
• In our RT-PCR assay, 7 (14%) (3 of 4 myxoid liposarcomas, 3 of 7 leiomyosarcomas, 1 of 9 malignant fibrous histiocytomas) of 50 sarcomas examined had no or a reduced expression of the h-warts/LATS1, indicating down-regulated gene expression [2].
• SDS-PAGE analysis revealed a complex of two polypeptides, mol. wts 25,000 and 12,000, here termed s-BLAST-2 [29].
• Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a Drosophila tumor suppressor [30].
• Effects on the thyroid of the mouse were monitored by the in vivo bioassay for LATS [31].

References