Download Gene Section LATS1 (LATS, large tumor suppressor, homolog 1 (Drosophila))

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LATS1 (LATS, large tumor suppressor, homolog 1
(Drosophila))
Stacy Visser, Xiaolong Yang
Department of Pathology and Molecular Medicine, Queen's University Kingston, ON, Canada (SV, XY)
Published in Atlas Database: May 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/LATS1ID41127ch6q25.html
DOI: 10.4267/2042/44735
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
domain lie two conserved residues, Ser909 and
Thr1079, which are phosphorylated upon activa-tion.
The N-terminus of LATS1 contains two PPxY motifs,
which bind to WW-domain transcriptional coactivators 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.
Identity
Other names: EC 2.7.11.1; WARTS; h-warts; wts
HGNC (Hugo): LATS1
Location: 6q25.1
Local order: KATNA1 - LATS1 - LOC645967 NUP43
DNA/RNA
Description
The LATS1 gene contains 8 exons, ranging in size
from 106 bp to 1513 bp. The mRNA transcript spans
4756 bp.
Expression
Transcription
Localisation
An alternatively spliced variant was identified in
vertebrate retina and testis. This smaller variant has
deletions of exon 6, 7, and 8. The functional
significance of this splice variant is not known.
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.
Protein
Function
LATS1 is ubiquitously expressed.
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
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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4)
397
LATS1 (LATS, large tumor suppressor, homolog 1 (Drosophila))
Visser S, Yang X
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. Down-stream of LATS1 lay two
transcriptional co-activators, YAP and TAZ, which are
phosphoryla-ted 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).
Function-ally, the Hippo-LATS pathway has been
implicated in cell proliferation, apoptosis, the epithelial
mesen-chymal transition, and cell migration.
Implicated in
Cancers
Disease
There is increasing evidence that LATS1 is
downregulated in a variety of human tumor types. To
date, loss of LATS1 has been found in soft tissue
sarcomas,
particularly
myxoid
liposarcoma,
leiomyosarcoma, and malignant fibrous histocyto-mas,
as well as ovarian cancer, breast cancer, acute
lymphoblastic leukemia, and astrocytoma. Prima-rily
downregulation of LATS1 expression is due to
hypermethylation of the promoter region.
Prognosis
Decreased LATS1 expression in breast cancer is
associated with large tumor size, high lymph node
metastasis, and estrogen and progesterone nega-tivity.
Thus, loss of LATS1 is associated with poor prognosis
in breast cancer. Furthermore, loss of LATS1
expression, in addition to other genes, can be used as a
prognostic factor in predicting disease-free survival for
acute lymphoblastic leukemia.
References
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. 1999 Feb;21(2):177-81
Homology
The LATS1 kinase domain is conserved across species.
Human homologs include LATS2 and the nuclear
Dbf2-related kinases, NDR1 and NDR2.
Turenchalk GS, St John MA, Tao W, Xu T. The role of lats in
cell cycle regulation and tumorigenesis. Biochim Biophys Acta.
1999 Oct 29;1424(2-3):M9-M16
Mutations
Hirota T, Morisaki T, Nishiyama Y, Marumoto T, Tada K, Hara
T, Masuko N, Inagaki M, Hatakeyama K, Saya H. Zyxin, a
regulator of actin filament assembly, targets the mitotic
apparatus by interacting with h-warts/LATS1 tumor suppressor.
J Cell Biol. 2000 May 29;149(5):1073-86
Note
There have been no reports of mutations in LATS1.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4)
398
LATS1 (LATS, large tumor suppressor, homolog 1 (Drosophila))
Visser S, Yang X
Yang X, Li DM, Chen W, Xu T. Human homologue of
Drosophila lats, LATS1, negatively regulate growth by inducing
G(2)/M arrest or apoptosis. Oncogene. 2001 Oct
4;20(45):6516-23
Hergovich A, Schmitz D, Hemmings BA. The human tumour
suppressor LATS1 is activated by human MOB1 at the
membrane. Biochem Biophys Res Commun. 2006 Jun
23;345(1):50-8
Hisaoka M, Tanaka A, Hashimoto H. Molecular alterations of hwarts/LATS1 tumor suppressor in human soft tissue sarcoma.
Lab Invest. 2002 Oct;82(10):1427-35
Jiang Z, Li X, Hu J, Zhou W, Jiang Y, Li G, Lu D. Promoter
hypermethylation-mediated down-regulation of LATS1 and
LATS2 in human astrocytoma. Neurosci Res. 2006
Dec;56(4):450-8
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. 2004 Jul 8;23(31):5266-74
Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor
suppressor LATS1 is a negative regulator of oncogene YAP. J
Biol Chem. 2008 Feb 29;283(9):5496-509
Lei QY, Zhang H, Zhao B, Zha ZY, Bai F, Pei XH, Zhao S,
Xiong Y, Guan KL. TAZ promotes cell proliferation and
epithelial-mesenchymal transition and is inhibited by the hippo
pathway. Mol Cell Biol. 2008 Apr;28(7):2426-36
Roman-Gomez J, Jimenez-Velasco A, Castillejo JA, Agirre X,
Barrios M, Navarro G, Molina FJ, Calasanz MJ, Prosper F,
Heiniger A, Torres A. Promoter hypermethylation of cancerrelated genes: a strong independent prognostic factor in acute
lymphoblastic leukemia. Blood. 2004 Oct 15;104(8):2492-8
Zeng Q, Hong W. The emerging role of the hippo pathway in
cell contact inhibition, organ size control, and cancer
development in mammals. Cancer Cell. 2008 Mar;13(3):188-92
Yang X, Yu K, Hao Y, Li DM, Stewart R, Insogna KL, Xu T.
LATS1 tumour suppressor affects cytokinesis by inhibiting
LIMK1. Nat Cell Biol. 2004 Jul;6(7):609-17
Zhang J, Smolen GA, Haber DA. Negative regulation of YAP
by LATS1 underscores evolutionary conservation of the
Drosophila Hippo pathway. Cancer Res. 2008 Apr
15;68(8):2789-94
Chan EH, Nousiainen M, Chalamalasetty RB, Schäfer A, Nigg
EA, Silljé HH. The Ste20-like kinase Mst2 activates the human
large tumor suppressor kinase Lats1. Oncogene. 2005 Mar
17;24(12):2076-86
This article should be referenced as such:
Takahashi Y, Miyoshi Y, Takahata C, Irahara N, Taguchi T,
Tamaki Y, Noguchi S. 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. 2005 Feb 15;11(4):1380-5
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(4)
Visser S, Yang X. LATS1 (LATS, large tumor suppressor,
homolog 1 (Drosophila)). Atlas Genet Cytogenet Oncol
Haematol. 2010; 14(4):397-399.
399