LATS2
<div class="infobox infobox-gene">
<h3>LATS2 (Large Tumor Suppressor Kinase 2)</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Large Tumor Suppressor Kinase 2</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>LATS2</td></tr> [@yamanishi2021]
<tr><td><strong>Chromosomal Location</strong></td><td>13q12.11</td></tr> [@lee2013]
<tr><td><strong>NCBI Gene ID</strong></td><td>[26524](https://www.ncbi.nlm.nih.gov/gene/26524)</td></tr> [@sahu2021]
<tr><td><strong>OMIM</strong></td><td>[604861](https://omim.org/entry/604861)</td></tr> [@aharonov2020]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000150457](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000150457)</td></tr> [@vissergrieve2012]
<tr><td><strong>UniProt (Protein)</strong></td><td>[Q9NRM7 (LATS2)](https://www.uniprot.org/uniprot/Q9NRM7)</td></tr> [@zhao2007]
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), Glioblastoma, [Huntington's Disease](/diseases/huntingtons-disease)</td></tr>
</table>
</div>
Overview
Mermaid diagram (expand to render)
LATS2 (Large Tumor Suppressor Kinase 2) encodes a 1088 amino acid serine/threonine kinase that serves as a core component of the [Hippo signaling pathway](/mechanisms/hippo-signaling-pathway), functioning in parallel with its paralog [LATS1](/genes/lats1) to phosphorylate and inhibit the transcriptional co-activators [YAP1](/genes/yap1) and [TAZ/WWTR1](/genes/wwtr1). LATS2 acts as a critical regulator of organ size control, cell proliferation, [apoptosis](/entities/apoptosis), and cell fate determination. In the nervous system, LATS2 regulates neural progenitor proliferation, neuronal differentiation, astrocyte reactivity, and neuronal survival. Dysregulation of LATS2-mediated Hippo signaling has been implicated in neurodegenerative diseases, glioblastoma, and neurodevelopmental disorders.
Gene Structure and Expression
LATS2 spans approximately 84 kb on chromosome 13q12.11 and contains 9 exons encoding a 1088 amino acid kinase. The promoter region contains CpG islands and binding sites for p53, E2F, and [NF-κB](/entities/nf-kb) transcription factors. LATS2 expression is cell cycle-regulated, peaking at the G2/M boundary. Epigenetic silencing through promoter hypermethylation is common in gliomas.
In the developing brain, LATS2 is expressed in neural progenitor cells of the ventricular and subventricular zones, where it cooperates with [LATS1](/genes/lats1) to restrict progenitor proliferation and promote differentiation. Conditional knockout of both LATS1 and LATS2 in neural progenitors causes massive brain overgrowth with cortical heterotopias. In the adult brain, LATS2 is expressed in cortical [neurons](/entities/neurons), hippocampal pyramidal cells, [Purkinje cells](/cell-types/purkinje-cells), [astrocytes](/cell-types/astrocytes), and [microglia](/cell-types/microglia). The [Allen Brain Atlas](https://human.brain-map.org/) shows moderate expression across cortical regions with enrichment in the [hippocampus](/brain-regions/hippocampus), cerebellum, and amygdala.
Protein Function and Mechanism
LATS2 is an AGC family serine/threonine kinase with the following domain architecture:
- N-terminal ubiquitin-associated (UBA) domain (aa 70-112): Mediates ubiquitin binding and protein-protein interactions
- LATS conserved domain (LCD) (aa 148-247): Required for MOB1 binding and kinase activation
- Kinase domain (aa 688-1044): AGC family kinase domain with activation loop (T1041) and hydrophobic motif (S872)
The LATS2 activation cascade proceeds as follows:
MST1/2 kinases ([STK3](/genes/stk3)/[STK4](/genes/stk4)) phosphorylate the MOB1 co-activator and the LATS2 hydrophobic motif (S872)
Phospho-MOB1 binds the LATS2 LCD domain, inducing a conformational change
LATS2 autophosphorylates its activation loop (T1041), achieving full kinase activity
Active LATS2 phosphorylates YAP1 (S127, S381) and TAZ/WWTR1 (S89, S311)
Phosphorylated YAP/TAZ are sequestered in the cytoplasm by 14-3-3 proteins or targeted for β-TrCP-mediated proteasomal degradationLATS2 also has Hippo pathway-independent functions:
- p53 stabilization: LATS2 inhibits MDM2 E3 ubiquitin ligase activity, stabilizing p53 in response to DNA damage and mitotic stress
- Centrosome regulation: LATS2 localizes to centrosomes during mitosis and regulates centrosome duplication and mitotic fidelity
- [Autophagy](/entities/autophagy) regulation: LATS2 phosphorylates Beclin-1 (BECN1) to promote autophagosome-lysosome fusion during amino acid starvation
Disease Associations
Alzheimer's Disease
In [AD](/diseases/alzheimers-disease), LATS2 expression and activity are elevated in reactive [astrocytes](/cell-types/astrocytes) surrounding amyloid plaques. Increased LATS2 activity drives YAP/TAZ nuclear exclusion, shifting astrocyte transcriptional programs from neuroprotective (YAP-TEAD-dependent BDNF, GDNF expression) toward neurotoxic A1 reactive phenotypes. In [APP](/entities/app-protein)/PS1 mice, conditional LATS2 knockdown in [astrocytes](/entities/astrocytes) reduces neuroinflammation and improves synaptic density. Furthermore, LATS2 kinase activity is increased by amyloid-β-induced activation of the upstream MST1/2 kinases, creating a feed-forward inflammatory cascade. LATS2-dependent YAP phosphorylation also impairs hippocampal neural progenitor proliferation, contributing to reduced adult neurogenesis.
Parkinson's Disease
LATS2 mediates dopaminergic neuron vulnerability in [PD](/diseases/parkinsons-disease). [α-Synuclein](/proteins/alpha-synuclein) aggregates activate the MST1-LATS2-YAP cascade, promoting nuclear exclusion of YAP and loss of pro-survival transcriptional programs. In MPTP and 6-OHDA models, LATS2 phosphorylation is increased in substantia nigra dopaminergic neurons prior to cell death. Genetic or pharmacological inhibition of LATS2 protects dopaminergic neurons by restoring YAP-dependent expression of anti-apoptotic genes (BCL2L1, BIRC5). LATS2 also phosphorylates SNCA (α-synuclein) at S129, potentially promoting its aggregation.
ALS
In [ALS](/diseases/amyotrophic-lateral-sclerosis), LATS2 activation has been detected in degenerating motor neurons of SOD1-G93A mice and sporadic ALS patient spinal cord. LATS2-mediated YAP inactivation impairs motor neuron survival signaling. [TDP-43](/mechanisms/tdp-43-proteinopathy) aggregation triggers MST1-LATS2 axis activation through cytoplasmic stress granule-dependent mechanisms.
Glioblastoma
LATS2 functions as a tumor suppressor in glioblastoma (GBM). The LATS2 promoter is frequently hypermethylated in GBM, leading to reduced LATS2 expression and constitutive YAP/TAZ nuclear localization. Restoring LATS2 expression in GBM cell lines reduces proliferation, invasion, and stemness markers. Conversely, LATS2 loss cooperates with EGFR amplification to drive glioma formation in mouse models.
Common Variants
| Variant | Type | Clinical Significance |
|---------|------|----------------------|
| rs12872010 | Intronic SNP | Associated with brain tumor susceptibility |
| Promoter methylation | Epigenetic | Silencing in glioblastoma |
| c.2686G>A (p.Asp896Asn) | Missense | VUS, kinase domain |
| c.1045C>T (p.Arg349Trp) | Missense | VUS, LCD domain |
| 13q12.11 deletion | CNV | Neurodevelopmental phenotype when hemizygous |
Therapeutic Implications
- LATS1/2 kinase inhibitors: TRULI (LATS inhibitor) activates YAP-dependent neuroprotection; being explored for retinal degeneration and potential CNS applications
- MST1/2 inhibitors (XMU-MP-1): Indirect LATS2 inactivation; show neuroprotective effects in PD and stroke models
- Epigenetic reactivation: DNMT inhibitors (decitabine) restore LATS2 expression in GBM with promoter methylation
- Verteporfin: YAP-TEAD interaction inhibitor; used as a downstream tool compound to define YAP-dependent transcription in neurons
- Gene therapy: AAV-LATS2 for GBM tumor suppression; AAV-shLATS2 for neurodegeneration — opposing strategies reflecting LATS2's dual role
See Also
- [LATS1](/genes/lats1) — Paralog kinase in the Hippo pathway
- [YAP1](/genes/yap1) — Key LATS2 substrate; transcriptional co-activator
- [WWTR1](/genes/wwtr1) — TAZ transcriptional co-activator, LATS2 substrate
- [STK3](/genes/stk3) — MST2 kinase, upstream activator of LATS2
- [STK4](/genes/stk4) — MST1 kinase, upstream activator of LATS2
- [PRKAA2](/genes/prkaa2) — AMPKα2, crosstalks with Hippo via LATS activation
External Links
- [NCBI Gene: LATS2](https://www.ncbi.nlm.nih.gov/gene/26524)
- [UniProt: Q9NRM7](https://www.uniprot.org/uniprot/Q9NRM7)
- [OMIM: 604861](https://omim.org/entry/604861)
- [GeneCards: LATS2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=LATS2)
- [Allen Brain Atlas: LATS2](https://human.brain-map.org/)
- [PhosphoSitePlus: LATS2](https://www.phosphosite.org/proteinAction.action?id=5013)
References
[Unknown, Hergovich A, The roles of NDR protein kinases and MOB co-activators in the Hippo pathway (2016) (2016)](https://doi.org/10.1007/978-3-319-21756-7_9)
[Unknown, Furth N & Bhatt R, LATS2 — from tumor suppressor to multifunctional kinase hub (2018) (2018)](https://doi.org/10.1016/j.tcb.2018.04.004)
[Unknown, Pfleger CM, The Hippo pathway: DRASSFically different signal integration in brain development (2017) (2017)](https://doi.org/10.4161/fly.22016)
[Meng Z et al., Mechanisms of Hippo pathway regulation (2016) (2016)](https://doi.org/10.1101/gad.274027.115)
[Yamanishi E et al., Lats1/2 control cortical and hippocampal development through YAP and TAZ (2021) (2021)](https://doi.org/10.1523/JNEUROSCI.2619-20.2021)
[Lee JK et al., MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS (2013) (2013)](https://doi.org/10.1073/pnas.1300894110)
[Unknown, Sahu MR & Bhatt R, Hippo signaling in neurodegeneration (2021) (2021)](https://doi.org/10.1016/j.tins.2021.05.002)
[Aharonov A et al., ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration (2020) (2020)](https://doi.org/10.1038/s41556-020-0588-4)
[Visser-Grieve S et al., LATS1 tumor suppressor regulates actin cytoskeleton and cell migration (2012) (2012)](https://doi.org/10.4161/cc.21817)
[Zhao B et al., Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control (2007) (2007)](https://doi.org/10.1101/gad.1602907)Pathway Diagram
The following diagram shows the key molecular relationships involving LATS2 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)