LATS2 (LATS, large tumor suppressor, homolog 2 (Drosophila))

2010-01-01   Damjan Glavač , Mojca Stražišar 

Department of Molecular genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Identity

HGNC
LOCATION
13q12.11
IMAGE
Atlas Image
LEGEND
UBA: ubiquitin-associated domain, PK: protein kinase domain, AGC: AGC-C terminal domain, Nu-B: NB-nucleotide binding domain.
LOCUSID
ALIAS
KPM
FUSION GENES

DNA/RNA

Note

Type: functioning gene, 8 exons.
Atlas Image
Filled blocks: coding exons, white blocks: non-coding exons, line: intron region, Ex: exon, In: intron, bp: base pair, kb: kilobase.

Description

Yabuta et al. (2000) mapped the human LATS2 gene to 13q11-q12 (FISH); gene with protein product. Gene encodes a serine/threonine protein kinase belonging to the LATS tumor suppressor family.

Pseudogene

Not known; paralogs according to Ensembl: LATS1, ROCK1, ROCK2.

Proteins

Note

LATS2 is a nuclear protein of approximately 120 kDa and 1088 AA. The protein localizes to centrosomes during interphase, and early and late metaphase. It interacts with the centrosomal proteins aurora-A and Ajuba and is required for accumulation of gamma-tubulin and spindle formation at the onset of mitosis. It also interacts with a negative regulator of TP53 and may function in a positive feedback loop with TP53 that responds to cytoskeleton damage. Additionally, it can function as a co-repressor of androgen-responsive gene expression.
Atlas Image
UBA: ubiquitin-associated domain, STK: serin/threonin kinase domain, AGC: AGC- C terminal domain, Ab: ATP-binding domain, AA: amino acid, P-Ser: phosphorylated serine, P-Thr: phosphorylated threonine, ATP-b: ATP binding site, Pa: proton acceptor.

Description

LATS2 protein is a serine/threonine protein kinase, 1088 AA; 120kDa; cofactor is magnesium. Subunit interacts and is phosphorylated by STK6. LATS2 binds to AR and interacts to JUB during mitosis. Complex regulates spindle apparatus organisation through gamma-tubulin recruitment to the centrosome. Protein is auto-phosphorylated and phosphorylated during M- and G1/S- phase of cell cycle; phosphorylated and activated by STK3.

Expression

Expressed at high levels in heart and skeletal muscle and at lower levels in all other tissues examined. Gene is found in cDNA libraries from the following tissue types: b-cell, bone, bone marrow, brain, cartilage, cerebrum, colon, ear, embryonic tissue, eye, foetus, gastrointestinal tract, heart, kidney, liver, lung, lymph node, lympho-reticular, mammary gland, muscle, nervous, ovary, pancreas, pancreatic islet, peripheral nervous system, placenta, pooled tissue, prostate, skin, spleen, stem cell, stomach, t-cell, testis, uncharacterized tissue, uterus, vascular.

Localisation

Cytoplasm, nucleus, spindle pole, centrosome; co-localizes with STK6 at the centrosomes during interphase, early pro-phase and cytokinesis. Migrates to spindle poles during mitosis, and to the mid-body during cytokinesis. S83 of Lats2 is a phosphorylation target of Aurora-A and the phosphorylation plays a role of the centrosomal localization of Lats2 (Toji et al., 2004).

Function

Protein product involved in: G1/S transition of mitotic cell cycle, hormone-mediated signalling pathway; negative regulation of Cyclin-dependent protein kinase activity; protein amino acid phosphorylation; protein kinase cascade; centrosome localisation; ATP binding; Mg-ion binding, nucleotide binding, protein serine/threonine kinase activity; protein tyrosine kinase activity; transferase activity; negative regulation of androgen receptor activity. LATS2 is a tumour suppressor that plays critical role in centrosome duplication, maintenance of mitotic fidelity and genomic stability. Negatively regulates G1/S transition by down-regulating cyclin E/CDK2 kinase activity.
LATS2 is involved in conserved Hippo signalling pathway (Zhang et al., 2008; Hergovich et al., 2009). LATS2 has an essential role in the integrity of processes that govern centrosome duplication, mitotic fidelity and genomic stability (McPherson et al., 2004). Components of the pathway bring LATS2 in contact with MST1 and MST2 kinase, which phosphorylates and activates LATS2. Functionally, pathway with LATS2 included is involved in cell proliferation, apoptosis, and cell migration. Involvement in apoptosis has been demonstrated in lung cancer cells where LATS2 has been shown to induce apoptosis through down regulation of BCL-2 and BCL-XL (BCL2L1) anti-apoptotic proteins (Ke et al., 2004).
LATS2 has been reported to inhibit cell growth by causing G1/S and/or G2/M cycle arrest (Li et al., 2003; Kamikubo et al., 2003). LATS2 binds MDM2 and with inhibiting its E3 ligase activity activates TP53. In turn TP53 rapidly and selectively up-regulates LATS2 expression in G2/M cells, defining positive feedback loop. Therefore LATS2-MDM2-TP53 constitutes a novel checkpoint pathway critical for maintenance of proper chromosome number (Aylon et al., 2007). LATS2 is also associated with Ajuba in LATS2-Ajuba complex that regulates organization of the spindle apparatus through recruitment of γ-tubulin to the centrosome (Abe et al., 2006).
In vitro over expression of LATS2 was seen to cause G1/S arrest through the inhibition of CDK2 activity (Li et al., 2003). Complete LATS2 knock-out cells exhibit an acceleration of exit from mitosis and marked down-regulation of critical mitotic regulators, proving its role in coordinating accurate cytokinesis completion, governing the stabilization of other regulators of mitosis (Yabuta at al., 2007). Study of LATS2 knock-out cells and transient co-expression of LATS2, YAP and TP73 showed that LATS2 contributes to the stability of YAP2 (YAP1) and TP73, which is dependant on the kinase function leading to the conclusion that LATS2 is involved in the fate of TP73 through YAP2 (Kawahara et al., 2008).

Mutations

Atlas Image
Position of alterations marked on the exons; length and position of the coding region described according to the exons.

Germinal

No data.

Somatic

Mutations are rare and mostly found in cancerous tissue. More frequently hypermethylation of the LATS2 promoter and or down-regulation of the expression is related to different kind of cancers (lung, breast, hepatocellular, leukaemias, testicular, astrocytomas, retinoblastoma, head and neck).
When polymorphism is noted or when dbSNP entrance number is provided, alterations are listed as polymorphisms; references are those when the alteration was first published.
1-59_70delT polymorphism Strazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62
119G>A (G40E) in lung adenocarcinoma cell line   Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8; 446(7132): 153-8.
1-203G/T

polymorphism

Strazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62
272C>T (S91L)dbSNP rs55842804Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8; 446(7132): 153-8.
ins 472_479 APpolymorphismStrazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62
del 472_479 APAPAPAP Strazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62
971C>T (A324V) dbSNP rs558614 Yabuta N, Fujii T, Copeland NG, et al. Structure, expression, and chromosome mapping of LATS2, a mammalian homologue of the Drosophila tumor suppressor gene lats/warts. Genomics. 2000 Jan 15; 63(2): 263-70.
1087G>A (G363S) dbSNP rs2770928 
1899+145A/G polymorphismStrazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62

2133C>T (V711V)

  
2395A>G (I799V)

dbSNP rs35368391 

Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8; 446(7132): 153-8.
2775G>A (V925V) in lung adenocarcinoma cell line  Sanger
2859C>A (C953Ter) in ovary mucinous carcinoma (not specified) Sanger
2892C>T (A964A)  Strazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62
3041C>G (A1014G)dbSNP rs45523141Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8; 446(7132): 153-8.
3074T>C (L1025P)dbSNP rs56116059Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8; 446(7132): 153-8.
3219C>A (S1073R) Strazisar M, Mlakar V, Glavac D. LATS2 tumour specific mutations and down-regulation of the gene in non-small cell carcinoma. Lung Cancer. 2009; 64(3): 257-62

Implicated in

Entity name
Various cancers
Note
Loss of LATS2 in mice is lethal. Knockout of the gene in mice embryonic fibroblasts induces mitotic defects, genomic instability and loss of contact inhibition (McPherson et al., 2004; Yabuta et al., 2007). Over-expression of LATS2 inhibits tumour formation in mice, or reduces cell growth in human tumour cell lines (Yang et al., 2001; Xia et al., 2002; Li et al., 2003) and on the other hand mutations and/or reduced expression (either methylation or miRNA regulation or unknown) have been observed in variety of human cancers; leukaemia (Jimenez-Velasco et al., 2005), astrocytomas (Jiang et al., 2006), prostate (Powzaniuk et al., 2004), breast (Takahashi et al., 2005), lung (Strazisar et al., 2009), head and neck (Steinmann et al., 2009), retinoblastoma (Chaktaborty et al., 2007), oesophageal (Lee et al., 2009), hepatocellular (Chen et al., 2005) and possibly also colon (Sivarajasingham et al., 2003) cancer. Frequent LOH of the gene has been observed in breast, ovary and liver cancer (Lee et al., 1988; Sato et al., 1991; Wang and Roger, 1988).
Entity name
Breast cancer
Note
Reduced expression of LATS2 mRNA is associated with biologically aggressive phenotypes of breast cancer, indicating that the reduced function of LATS2 can lead to accelerated cell proliferation and have as a result higher incidence of distant metastases (Takahashi et al., 2005). LATS2 mRNA levels were in 2007 discovered to be clinically useful for the prediction of response to epirubicin plus cyclophosphamide treatment in breast cancer patients (Takahashi et al., 2007).
Entity name
Acute lymphoblastic leukaemia
Prognosis
Down regulation mainly by aberrant promoter methylation of LATS2 is also associated with poor prognosis in acute lymphoblastic leukaemia (Jimenez-Velasco et al., 2005).
Entity name
Testicular and prostate tumours
Note
In testicular germ cell tumours miRNAs (miR-372 and miR-373) were implicated in neutralization of TP53-mediated CDK inhibition, through direct inhibition of the expression of LATS2 (Voorhoeve et al., 2006). It has been also shown that LATS2 is down regulated in human testicular cancer cells (Vorhoeve et al., 2006; Duale et al., 2007). LATS2 functions also as negative regulator of AR (androgen receptor), which plays an essential role in the development and maintenance of the male reproductive system and in prostate cancer. It has been shown that expression of LATS2 is lower in human prostate tumours, and suggested to contribute to the development of prostate cancer through regulation AR-mediated transcription (Powzaniuk et al., 2004).
Entity name
Astrocytomas
Note
Methylation of LATS2 and down regulation was detected in astrocytomas and proposed as a useful target for astrocytomas therapy by Jiang et al. (2006).
Entity name
Oesophageal squamous cell carcinoma
Note
Frequent polymorphic changes but rare tumour specific mutations of the LATS2 gene were found in oesophageal squamous cell carcinoma, indicating LATS2 is inactivated in only small parts of oesophageal tumours (Ishizaki et al., 2002).
Entity name
Non-small cell lung cancer
Note
Down regulation of LATS2 have been found in non-small cell lung cancer and mutations discovered have been related mostly to squamous lung cell carcinomas (Strazisar et al., 2009a; Strazisar et al., 2009b).

Bibliography

Pubmed IDLast YearTitleAuthors
164135472006LATS2-Ajuba complex regulates gamma-tubulin recruitment to centrosomes and spindle organization during mitosis.Abe Y et al
170154312006A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization.Aylon Y et al
198554282009Silencing of the Lats2 tumor suppressor overrides a p53-dependent oncogenic stress checkpoint and enables mutant H-Ras-driven cell transformation.Aylon Y et al
182364732008Pharmacogenomic profile of soy isoflavone concentrate in the prostate of Nrf2 deficient and wild-type mice.Barve A et al
176045972007Identification of genes associated with tumorigenesis of retinoblastoma by microarray analysis.Chakraborty S et al
156880062005The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.Chan EH et al
160754622005Molecular genetic evidence supporting a novel human hepatocellular carcinoma tumor suppressor locus at 13q12.11.Chen CF et al
198421742009Comparative expression of zebrafish lats1 and lats2 and their implication in gastrulation movements.Chen CH et al
197391192010Molecular characterization of human homologs of yeast MOB1.Chow A et al
170681542007Gene-expression profiling and array-based CGH classify CD4+CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities.Dijkman R et al
177115792007Molecular portrait of cisplatin induced response in human testis cancer cell lines based on gene expression profiles.Duale N et al
173213322007Combined translocation with ZNF198-FGFR1 gene fusion and deletion of potential tumor suppressors in a myeloproliferative disorder.Etienne A et al
183919852008Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy.Finkin S et al
188024032008Mdm2 exerts pro-apoptotic activities by antagonizing insulin-like growth factor-I-mediated survival.Froment P et al
173448462007Patterns of somatic mutation in human cancer genomes.Greenman C et al
194847422009Mammalian NDR/LATS protein kinases in hippo tumor suppressor signaling.Hergovich A et al
108718632000Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a Drosophila tumor suppressor.Hori T et al
193325592009TTK/hMps1 mediates the p53-dependent postmitotic checkpoint by phosphorylating p53 at Thr18.Huang YF et al
123707542002Frequent polymorphic changes but rare tumor specific mutations of the LATS2 gene on 13q11-12 in esophageal squamous cell carcinoma.Ishizaki K et al
170496572006Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma.Jiang Z et al
162084122005Downregulation of the large tumor suppressor 2 (LATS2/KPM) gene is associated with poor prognosis in acute lymphoblastic leukemia.Jiménez-Velasco A et al
126241012003Inhibition of cell growth by conditional expression of kpm, a human homologue of Drosophila warts/lats tumor suppressor.Kamikubo Y et al
185658512008Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73.Kawahara M et al
152656832004Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-x(L).Ke H et al
156755722005[Aurora kinases and cancer].Kimura M et al
195015852009MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer.Lee KH et al
128539762003Lats2, a putative tumor suppressor, inhibits G1/S transition.Li Y et al
189274642008Lats2 is a negative regulator of myocyte size in the heart.Matsui Y et al
153432672004Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity.McPherson JP et al
182814752008Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14.Ouillette P et al
151312602004The LATS2/KPM tumor suppressor is a negative regulator of the androgen receptor.Powzaniuk M et al
175389462007Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma.Seidel C et al
145974492003Identifying a region of interest in site- and stage-specific colon cancer on chromosome 13.Sivarajasingham NS et al
198856082009Frequent promoter hypermethylation of tumor-related genes in head and neck squamous cell carcinoma.Steinmann K et al
192383342009The expression of COX-2, hTERT, MDM2, LATS2 and S100A2 in different types of non-small cell lung cancer (NSCLC).Strazisar M et al
172976102007Low LATS2 mRNA level can predict favorable response to epirubicin plus cyclophosphamide, but not to docetaxel, in breast cancers.Takahashi Y et al
151472692004The centrosomal protein Lats2 is a phosphorylation target of Aurora-A kinase.Toji S et al
197999732010Identification of LATS transcriptional targets in HeLa cells using whole human genome oligonucleotide microarray.Visser S et al
176957192007A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.Voorhoeve PM et al
106733372000Structure, expression, and chromosome mapping of LATS2, a mammalian homologue of the Drosophila tumor suppressor gene lats/warts.Yabuta N et al
174784262007Lats2 is an essential mitotic regulator required for the coordination of cell division.Yabuta N et al
184137462008Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway.Zhang J et al
195842862009Transcriptional output of the Salvador/warts/hippo pathway is controlled in distinct fashions in Drosophila melanogaster and mammalian cell lines.Zhang X et al
198788662009Mst out and HCC in.Zhao B et al

Other Information

Locus ID:

NCBI: 26524
MIM: 604861
HGNC: 6515
Ensembl: ENSG00000150457

Variants:

dbSNP: 26524
ClinVar: 26524
TCGA: ENSG00000150457
COSMIC: LATS2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000150457ENST00000382592Q9NRM7
ENSG00000150457ENST00000382592A0A024RDM3

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Hippo signaling pathwayKEGGhsa04390
Hippo signaling pathwayKEGGko04390
Hippo signalingKEGGhsa_M00683
Hippo signalingKEGGM00683
Signal TransductionREACTOMER-HSA-162582
Signaling by HippoREACTOMER-HSA-2028269
Hippo signaling pathway -multiple speciesKEGGko04392
Hippo signaling pathway -multiple speciesKEGGhsa04392

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
156880062005The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1.214
157460362005Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.112
250262112014Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus.88
218321542011Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor.85
231113892012MiR-93 enhances angiogenesis and metastasis by targeting LATS2.84
269086282016Long Noncoding RNA PVT1 Promotes Non-Small Cell Lung Cancer Cell Proliferation through Epigenetically Regulating LATS2 Expression.83
212332122011KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.73
212450962011LATS2 is a tumor suppressor gene of malignant mesothelioma.72
128539762003Lats2, a putative tumor suppressor, inhibits G1/S transition.66
195015852009MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer.65

Citation

Damjan Glavač ; Mojca Stražišar

LATS2 (LATS, large tumor suppressor, homolog 2 (Drosophila))

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/41128/lats2-(lats-large-tumor-suppressor-homolog-2-(drosophila))