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| Description | LATS1 is a highly conserved Ser/Thr kinase that belongs to the AGC (Protein kinase A/G/C) family of protein kinases. Within the C-terminal kinase domain lie two conserved residues, Ser909 and Thr1079, which are phosphorylated upon activation. The N-terminus of LATS1 contains two PPxY motifs, which bind to WW-domain transcriptional co-activators TAZ and YAP, as well as a protein binding domain (PBD) that has been shown to bind to MOB1 and cytoskeletal proteins LIMK1 and Zyxin. In addition, an ubiquitin binding domain (UBA) and a proline-rich region (P-stretch) have been identified in the N-terminal region of LATS1, although the functional significance of these domains has not yet been determined. |
| Expression | LATS1 is ubiquitously expressed. |
| Localisation | LATS1 is primarily localized within the cytoplasm, however, LATS1 possesses functions that require its translocation to the nucleus. The mechanism of translocation is not yet understood. |
| Function | As a tumor suppressor, LATS1 functions as a key regulator of cell cycle progression, apoptosis, and cell migration. As cell cycle regulator, LATS1 is able to modulate multiple aspects of the cell cycle, including G2/M arrest, mitotic exit, activation of the G1 tetraploidy checkpoint, and regulation of cytokinesis. LATS1 also promotes apoptosis by inducing expression of pro-apoptotic proteins BAX, caspase 3 and tumor suppressor p53. Finally, loss of LATS1 has been shown to enhance the rate of cell migration. HIPPO-LATS Signaling Pathway : LATS1 is a key player in the conserved Hippo-LATS signaling pathway. Components of this pathway include the adaptor proteins WW45 and MOB, which aid in bringing LATS in contact with the kinase MST1/MST2. MST1/2 can then phosphorylate and activate LATS1. Upstream of MST1/2 lay FERM domain proteins Willin/FRMD6 and Merlin/NF2, as well as a protocadherin FAT4. The molecular mechanisms regulating this pathway have not yet been delineated in a mammalian system. Downstream of LATS1 lay two transcriptional co-activators, YAP and TAZ, which are phosphorylated and inhibited by LATS1, thereby sequestering them in the cytoplasm. Finally, YAP and TAZ have been shown to act through the TEAD/TEF family of transcription factors to modulate the expression of a variety of genes (See figure below). Functionally, the Hippo-LATS pathway has been implicated in cell proliferation, apoptosis, the epithelial mesenchymal transition, and cell migration. |
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| Homology | The LATS1 kinase domain is conserved across species. Human homologs include LATS2 and the nuclear Dbf2-related kinases, NDR1 and NDR2. |
| Human homologue of the Drosophila melanogaster lats tumour suppressor modulates CDC2 activity. |
| Tao W, Zhang S, Turenchalk GS, Stewart RA, St John MA, Chen W, Xu T. |
| Nat Genet. 1999 Feb;21(2):177-81. |
| PMID 9988268 |
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| The role of lats in cell cycle regulation and tumorigenesis. |
| Turenchalk GS, St John MA, Tao W, Xu T. |
| Biochim Biophys Acta. 1999 Oct 29;1424(2-3):M9-M16. (REVIEW) |
| PMID 10528150 |
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| Zyxin, a regulator of actin filament assembly, targets the mitotic apparatus by interacting with h-warts/LATS1 tumor suppressor. |
| Hirota T, Morisaki T, Nishiyama Y, Marumoto T, Tada K, Hara T, Masuko N, Inagaki M, Hatakeyama K, Saya H. |
| J Cell Biol. 2000 May 29;149(5):1073-86. |
| PMID 10831611 |
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| Human homologue of Drosophila lats, LATS1, negatively regulate growth by inducing G(2)/M arrest or apoptosis. |
| Yang X, Li DM, Chen W, Xu T. |
| Oncogene. 2001 Oct 4;20(45):6516-23. |
| PMID 11641775 |
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| Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. |
| Hisaoka M, Tanaka A, Hashimoto H. |
| Lab Invest. 2002 Oct;82(10):1427-35. |
| PMID 12379777 |
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| Tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G1 tetraploidy checkpoint function. |
| Iida S, Hirota T, Morisaki T, Marumoto T, Hara T, Kuninaka S, Honda S, Kosai K, Kawasuji M, Pallas DC, Saya H. |
| Oncogene. 2004 Jul 8;23(31):5266-74. |
| PMID 15122335 |
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| Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. |
| Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X, Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F, Heiniger A, Torres A. |
| Blood. 2004 Oct 15;104(8):2492-8. Epub 2004 Jun 15. |
| PMID 15198948 |
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| LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. |
| Yang X, Yu K, Hao Y, Li DM, Stewart R, Insogna KL, Xu T. |
| Nat Cell Biol. 2004 Jul;6(7):609-17. Epub 2004 Jun 27. |
| PMID 15220930 |
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| The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. |
| Chan EH, Nousiainen M, Chalamalasetty RB, Schafer A, Nigg EA, Sillje HH. |
| Oncogene. 2005 Mar 17;24(12):2076-86. |
| PMID 15688006 |
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| Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers. |
| Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T, Tamaki Y, Noguchi S. |
| Clin Cancer Res. 2005 Feb 15;11(4):1380-5. |
| PMID 15746036 |
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| The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. |
| Hergovich A, Schmitz D, Hemmings BA. |
| Biochem Biophys Res Commun. 2006 Jun 23;345(1):50-8. Epub 2006 Apr 25. |
| PMID 16674920 |
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| Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma. |
| Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D. |
| Neurosci Res. 2006 Dec;56(4):450-8. Epub 2006 Oct 17. |
| PMID 17049657 |
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| Tumor suppressor LATS1 is a negative regulator of oncogene YAP. |
| Hao Y, Chun A, Cheung K, Rashidi B, Yang X. |
| J Biol Chem. 2008 Feb 29;283(9):5496-509. Epub 2007 Dec 24. |
| PMID 18158288 |
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| TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway. |
| Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S, Xiong Y, Guan KL. |
| Mol Cell Biol. 2008 Apr;28(7):2426-36. Epub 2008 Jan 28. |
| PMID 18227151 |
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| The emerging role of the hippo pathway in cell contact inhibition, organ size control, and cancer development in mammals. |
| Zeng Q, Hong W. |
| Cancer Cell. 2008 Mar;13(3):188-92. (REVIEW) |
| PMID 18328423 |
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| Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. |
| Zhang J, Smolen GA, Haber DA. |
| Cancer Res. 2008 Apr 15;68(8):2789-94. |
| PMID 18413746 |
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