LATS1

Official Full Name

large tumor suppressor kinase 1

Organism

Homo sapiens

GeneID

9113

Background

The protein encoded by this gene is a putative serine/threonine kinase that localizes to the mitotic apparatus and complexes with cell cycle controller CDC2 kinase in early mitosis. The protein is phosphorylated in a cell-cycle dependent manner, with late prophase phosphorylation remaining through metaphase. The N-terminal region of the protein binds CDC2 to form a complex showing reduced H1 histone kinase activity, indicating a role as a negative regulator of CDC2/cyclin A. In addition, the C-terminal kinase domain binds to its own N-terminal region, suggesting potential negative regulation through interference with complex formation via intramolecular binding. Biochemical and genetic data suggest a role as a tumor suppressor. This is supported by studies in knockout mice showing development of soft-tissue sarcomas, ovarian stromal cell tumors and a high sensitivity to carcinogenic treatments. [provided by RefSeq, Apr 2017]

Synonyms

wts; WARTS;

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Detailed Information

Recent Progress

The Large Tumor Suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor that can be found down-regulated in various human cancers. LATS1 has recently been identified as a central player in Hippo signaling pathway, involving in organ size control, tumorigenesis, stem cell differentiation and renewal, etc. Although mounting evidences support the role of LATS1 in tumor suppression and tumorigenesis, however, the regulatory mechanisms of LATS1 at the molecular level are not fully understood. Several observations have revealed the key role of the Hippo pathway in modulating tumor immunogenicity and demonstrated a proof of concept for targeting LATS1/2 in cancer immunotherapy.

Fig. 1. Domain architecture of the LAST1. (Moroshi et al, 2016)

LATS1 expression is associated with hypermethylation of the colorectal cancer (CRC) promoter and microsatellite instability. Decreased LATS1 expression was found in 90.0% CRC cases. The expression is lowest in Dukes' B stage tumors and G1 (well-differentiated) cells. Hypermethylation of the LATS1 promoter was present in 58% of CRC patients. LATS1 promoter hypermethylation was strongly associated with decreased gene expression; the expression of LATS1 in methylated cases is significantly lower than that in un-methylated cases.

The clinical significance and biological function of LATS1 in non-small-cell lung cancer (NSCLC) have also been studied. Investigation of LATS1 in 136 cases of NSCLC tissue and 30 cases of normal lung tissue confirmed that LATS1 expression was higher in normal lung tissues, but significantly lower in NSCLC tissues. Moreover, the expression of LATS1 in NSCLC was significantly correlated with p-TNM stage and lymph node metastasis. Further studies of NSCLC cell lines in which LATS1 was overexpressed or depleted confirmed that LATS1 markedly inhibits cell proliferation and invasion, and regulates the nuclear location of yes-associated protein (YAP). These results indicate that LATS1 may serve as a novel therapeutic target for NSCLC.

Researchers have identified WWP1 E3 ligase is another novel negative regulator of LATS1 and confirmed that WWP1 is essential for the stability of LATS1 in vitro and in vivo. Importantly, it was also shown that degradation of LATS1 plays a key role in mediating WWP1-induced breast cancer cell proliferation. Since WWP1 is an oncogene and LATS1 is a tumor suppressor gene in breast cancer, these data provide a promising therapeutic strategy to inhibit breast cancer.

References:

Moroishi, Toshiro, et al. "The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity." Cell 167.6(2016):1525-1539.
Yeung, B, K. C. Ho, and X. Yang. "WWP1 E3 ligase targets LATS1 for ubiquitin-mediated degradation in breast cancer cells." Plos One 8.4(2013):e61027.
Wierzbicki, Piotr M, et al. "Underexpression of LATS1 TSG in colorectal cancer is associated with promoter hypermethylation." World Journal of Gastroenterology 19.27(2013):4363-4373.
Pefani, D. E., et al. "Erratum: RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2. " Nature Cell Biology 17.4(2015):962.
Lin, X. Y., et al. "Expression of LATS1 contributes to good prognosis and can negatively regulate YAP oncoprotein in non-small-cell lung cancer. " Tumour Biology 35.7(2014):6435-43.

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