LATS1 explained

Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.^{[1] [2] [3]}

It has been associated with the Hippo signaling pathway, where it phosphorylates YAP and TAZ to inactivate their function.^[4]

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 histone H1 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.^[3]

Interactions

LATS1 has been shown to interact with Zyxin^[5] and Cdk1.

Further reading

• Xu T, Wang W, Zhang S, etal . Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. . Development . 121 . 4 . 1053–63 . 1995 . 10.1242/dev.121.4.1053 . 7743921 .
• St John MA, Tao W, Fei X, etal . Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. . Nat. Genet. . 21 . 2 . 182–6 . 1999 . 9988269 . 10.1038/5965 . 11882936 .
• Nishiyama Y, Hirota T, Morisaki T, etal . A human homolog of Drosophila warts tumor suppressor, h-warts, localized to mitotic apparatus and specifically phosphorylated during mitosis. . FEBS Lett. . 459 . 2 . 159–65 . 1999 . 10518011 . 10.1016/S0014-5793(99)01224-7 . 22292346 . free .
• Hirota T, Morisaki T, Nishiyama Y, etal . Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. . J. Cell Biol. . 149 . 5 . 1073–86 . 2000 . 10831611 . 10.1083/jcb.149.5.1073 . 2174824 .
• Morisaki T, Hirota T, Iida S, etal . WARTS tumor suppressor is phosphorylated by Cdc2/cyclin B at spindle poles during mitosis. . FEBS Lett. . 529 . 2–3 . 319–24 . 2002 . 12372621 . 10.1016/S0014-5793(02)03360-4 . 45272429 .
• Hisaoka M, Tanaka A, Hashimoto H . Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma . Lab. Invest. . 82 . 10 . 1427–35 . 2002 . 12379777 . 10.1097/01.lab.0000032381.68634.ca. 34100799 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Kamikubo Y, Takaori-Kondo A, Uchiyama T, Hori T . Inhibition of cell growth by conditional expression of kpm, a human homologue of Drosophila warts/lats tumor suppressor . J. Biol. Chem. . 278 . 20 . 17609–14 . 2003 . 12624101 . 10.1074/jbc.M211974200 . free . 2433/148480 . free .
• Brill LM, Salomon AR, Ficarro SB, etal . Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry . Anal. Chem. . 76 . 10 . 2763–72 . 2004 . 15144186 . 10.1021/ac035352d .
• Yang X, Yu K, Hao Y, etal . LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1 . Nat. Cell Biol. . 6 . 7 . 609–17 . 2004 . 15220930 . 10.1038/ncb1140 . 20493738 .
• Beausoleil SA, Jedrychowski M, Schwartz D, etal . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proc. Natl. Acad. Sci. U.S.A. . 101 . 33 . 12130–5 . 2004 . 15302935 . 10.1073/pnas.0404720101 . 514446 . 2004PNAS..10112130B . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Chan EH, Nousiainen M, Chalamalasetty RB, etal . The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1 . Oncogene . 24 . 12 . 2076–86 . 2005 . 15688006 . 10.1038/sj.onc.1208445 . 27285160 .
• Takahashi Y, Miyoshi Y, Takahata C, etal . Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers . Clin. Cancer Res. . 11 . 4 . 1380–5 . 2005 . 15746036 . 10.1158/1078-0432.CCR-04-1773 . 23415582 .
• Kuninaka S, Nomura M, Hirota T, etal . The tumor suppressor WARTS activates the Omi / HtrA2-dependent pathway of cell death . Oncogene . 24 . 34 . 5287–98 . 2005 . 16007220 . 10.1038/sj.onc.1208682 . 25678521 .
• Bothos J, Tuttle RL, Ottey M, etal . Human LATS1 is a mitotic exit network kinase . Cancer Res. . 65 . 15 . 6568–75 . 2005 . 16061636 . 10.1158/0008-5472.CAN-05-0862 .
• Jiang Z, Li X, Hu J, etal . Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma . Neurosci. Res. . 56 . 4 . 450–8 . 2007 . 17049657 . 10.1016/j.neures.2006.09.006 . 22763208 .

Notes and References

1. Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T . Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity . Nat Genet . 21 . 2 . 177–81 . February 1999 . 9988268 . 10.1038/5960 . 32090556 .
2. Iida S, Hirota T, Morisaki T, Marumoto T, Hara T, Kuninaka S, Honda S, Kosai K, Kawasuji M, Pallas DC, Saya H . Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function . Oncogene . 23 . 31 . 5266–74 . July 2004 . 15122335 . 10.1038/sj.onc.1207623 . 25545351 .
3. Web site: Entrez Gene: LATS1 LATS, large tumor suppressor, homolog 1 (Drosophila).
4. Hao Y, Chun A, Cheung K, Rashidi B, Yang X . Tumor suppressor LATS1 is a negative regulator of oncogene YAP . J. Biol. Chem. . 283 . 9 . 5496–509 . February 2008 . 18158288 . 10.1074/jbc.M709037200 . free .
5. Hirota . T . Morisaki T . Nishiyama Y . Marumoto T . Tada K . Hara T . Masuko N . Inagaki M . Hatakeyama K . Saya H . May 2000 . Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor . J. Cell Biol. . 149 . 5 . 1073–86 . 0021-9525. 10831611 . 2174824. 10.1083/jcb.149.5.1073 .