LATS1 — Large Tumor Suppressor Kinase 1, Hippo Pathway

LATS1 — Large Tumor Suppressor Kinase 1, Hippo Pathway

<div class="infobox infobox-gene">
<h3>LATS1 (Large Tumor Suppressor Kinase 1)</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Large Tumor Suppressor Kinase 1</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>LATS1</td></tr> [@jiang2006]
<tr><td><strong>Chromosomal Location</strong></td><td>6q25.1</td></tr> [@fan2022]
<tr><td><strong>NCBI Gene ID</strong></td><td>[9113](https://www.ncbi.nlm.nih.gov/gene/9113)</td></tr> [@mao2021]
<tr><td><strong>OMIM</strong></td><td>[603473](https://omim.org/entry/603473)</td></tr> [@tanaka2020]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000131023](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131023)</td></tr> [@petrilli2016]
<tr><td><strong>UniProt (Protein)</strong></td><td>[O95835 (LATS1)](https://www.uniprot.org/uniprot/O95835)</td></tr> [@bi2022]
<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, Meningioma</td></tr>
</table>
</div>

Overview

LATS1 — Large Tumor Suppressor Kinase 1, Hippo Pathway

<div class="infobox infobox-gene">
<h3>LATS1 (Large Tumor Suppressor Kinase 1)</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Large Tumor Suppressor Kinase 1</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>LATS1</td></tr> [@jiang2006]
<tr><td><strong>Chromosomal Location</strong></td><td>6q25.1</td></tr> [@fan2022]
<tr><td><strong>NCBI Gene ID</strong></td><td>[9113](https://www.ncbi.nlm.nih.gov/gene/9113)</td></tr> [@mao2021]
<tr><td><strong>OMIM</strong></td><td>[603473](https://omim.org/entry/603473)</td></tr> [@tanaka2020]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000131023](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131023)</td></tr> [@petrilli2016]
<tr><td><strong>UniProt (Protein)</strong></td><td>[O95835 (LATS1)](https://www.uniprot.org/uniprot/O95835)</td></tr> [@bi2022]
<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, Meningioma</td></tr>
</table>
</div>

Overview

LATS1 (Large Tumor Suppressor Kinase 1) encodes a 1,130 amino acid serine/threonine kinase that is a core component of the Hippo signaling pathway — an evolutionarily conserved tumor suppressor cascade that controls organ size, cell proliferation, [apoptosis](/entities/apoptosis), and stem cell self-renewal. LATS1, together with its paralog [LATS2](/genes/lats2), directly phosphorylates and inactivates the transcriptional co-activators [YAP1](/genes/yap1) and [TAZ (WWTR1)](/genes/wwtr1), preventing their nuclear entry and transcriptional activity. In the nervous system, LATS1-mediated Hippo signaling regulates neural progenitor proliferation, neuronal morphogenesis, synaptic plasticity, astrocyte reactivity, and neuroinflammation. Emerging evidence links Hippo pathway dysregulation to [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and brain tumors, positioning LATS1 as a key node connecting developmental growth control to neurodegenerative pathology.

Gene Structure and Expression

LATS1 spans approximately 68 kb on chromosome 6q25.1 and contains 9 exons. The promoter contains a CpG island subject to epigenetic silencing by [DNA methylation](/entities/dna-methylation) in certain cancers. The gene is ubiquitously expressed, with notable enrichment in the brain, heart, and immune cells.

In the developing brain, LATS1 is expressed in neural progenitors of the ventricular and subventricular zones, where it controls the balance between proliferation and differentiation. In the adult brain, LATS1 is expressed in cortical and hippocampal [neurons](/entities/neurons), [astrocytes](/cell-types/astrocytes), [microglia](/cell-types/microglia), and [oligodendrocytes](/cell-types/oligodendrocytes). The [Allen Brain Atlas](https://human.brain-map.org/) shows moderate-to-high expression across the [hippocampus](/brain-regions/hippocampus), cerebral [cortex](/brain-regions/cortex), and cerebellum, with enrichment in the CA1 region and dentate gyrus.

Protein Function and Mechanism

LATS1 is an AGC family serine/threonine kinase comprising an N-terminal PAPA (proline/alanine-rich) domain, two conserved PPxY motifs for WW domain interactions, a ubiquitin-associated (UBA) domain, and a C-terminal kinase domain. Full activation requires sequential phosphorylation: [MST1](/genes/mst1)/MST2 ([STK3](/genes/stk3)) phosphorylate the LATS1 hydrophobic motif (T1079), followed by LATS1 autophosphorylation of its activation loop (S909).

Canonical Hippo Pathway

The Hippo signaling cascade proceeds as follows:

Non-Canonical Functions

Beyond YAP/TAZ, LATS1 phosphorylates additional substrates with neurological relevance:

• SNAI1 (Snail): LATS1 phosphorylation promotes Snail degradation, modulating epithelial-mesenchymal transition and neural crest cell migration
• DYRK1A: LATS1 interacts with and modulates the activity of [DYRK1A](/genes/dyrk1a), a kinase implicated in Down syndrome and [tau](/proteins/tau) phosphorylation
• p53: LATS1 stabilizes p53 by phosphorylating MDM2, linking Hippo signaling to DNA damage responses
• Rab8A: LATS1 phosphorylates Rab8A to regulate ciliogenesis, connecting Hippo to primary cilium formation

Upstream Regulation

LATS1 activity is modulated by diverse signals relevant to neurodegeneration:

• Cell density and contact inhibition: E-cadherin and α-catenin at adherens junctions activate LATS1 through [NF2 (Merlin)](/genes/nf2) and the KIBRA–FRMD6 complex
• Mechanical cues: Soft extracellular matrix activates LATS1, while stiff matrix inactivates it — relevant to brain stiffness changes in aging and neurodegeneration
• GPCRs: Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) signaling through Gα12/13 inhibits LATS1, while glucagon and epinephrine via Gαs activate it
• Energy stress: [AMPK](/genes/prkaa1) activation phosphorylates and activates LATS1 under energy-depleted conditions, linking metabolic sensing to Hippo signaling
• Oxidative stress: [ROS](/entities/reactive-oxygen-species) activate LATS1 via MST1/2 and c-Jun N-terminal kinase (JNK), an important mechanism in neurodegeneration

Role in Neural Development

LATS1 plays multiple roles in CNS development:

• Neural progenitor regulation: LATS1/2 control the size of the neural progenitor pool by restricting YAP-driven proliferation. Conditional LATS1/2 double knockout in neural progenitors causes massive brain overgrowth (megalencephaly) due to unrestrained YAP activation and TEAD-dependent transcription of cyclin and survivin genes
• Neuronal morphogenesis: LATS1 regulates dendrite arborization through phosphorylation of the actin cytoskeleton regulator LIMK1. LATS1 loss in hippocampal neurons leads to excessive dendritic branching
• Astrocyte differentiation: LATS1-mediated YAP phosphorylation promotes the transition from neural progenitor to astrocyte fate during late embryonic development by de-repressing astrogliogenic [STAT3](/genes/stat3) signaling
• Cerebellar development: LATS1 restricts granule neuron precursor proliferation in the external granular layer, and its loss cooperates with [SHH](/genes/shh)/[SMO](/genes/smo) pathway activation in medulloblastoma

Disease Associations

Alzheimer's Disease (AD)

Hippo pathway activity through LATS1 is significantly altered in [AD](/diseases/alzheimers-disease). Postmortem AD brain tissue shows decreased LATS1 phosphorylation (inactive kinase) and corresponding nuclear YAP accumulation in hippocampal neurons and reactive [astrocytes](/entities/astrocytes). Nuclear YAP drives expression of pro-inflammatory and cell cycle re-entry genes that are detrimental in post-mitotic neurons. Paradoxically, YAP also has neuroprotective functions: YAP–TEAD complexes upregulate [BDNF](/genes/bdnf) and anti-apoptotic [BCL-XL](/genes/bcl2l1), and YAP degradation by excessive LATS1 activity may deprive neurons of survival signals. This dual role complicates therapeutic targeting.

[Tau](/genes/mapt) pathology directly impairs Hippo signaling: hyperphosphorylated tau disrupts the MST1–SAV1 complex required for LATS1 activation, while [Aβ](/proteins/amyloid-beta) oligomers activate the LATS1 kinase through ROS-dependent MST1 activation, driving YAP phosphorylation and neuronal apoptosis. The net outcome — whether LATS1 hyperactivation is neurotoxic or neuroprotective — appears to be cell-type and stage-dependent, with LATS1 activation being harmful in neurons (driving YAP-dependent apoptosis) but potentially beneficial in reactive astrocytes (limiting YAP-driven A1 astrocyte proliferation).

Parkinson's Disease (PD)

In [PD](/diseases/parkinsons-disease) models, LATS1 is activated by [α-synuclein](/entities/snca)-induced oxidative stress, leading to YAP phosphorylation and cytoplasmic sequestration in dopaminergic neurons. LATS1-mediated YAP inactivation reduces expression of survival genes including [GDNF](/genes/gdnf) receptor components and mitochondrial quality control factors. MPTP-treated mice show elevated phospho-LATS1 (active) and phospho-YAP (inactive) in the substantia nigra pars compacta. Pharmacological LATS1 inhibition (using the tool compound TRULI) rescues YAP nuclear localization and dopaminergic neuron survival in vitro. Additionally, LATS1 regulates [PINK1](/genes/pink1)/[Parkin](/genes/prkn)-mediated mitophagy: LATS1 phosphorylation of Beclin-1 promotes the [autophagy](/entities/autophagy)–mitophagy switch, and LATS1 deficiency impairs selective mitochondrial clearance.

Amyotrophic Lateral Sclerosis (ALS)

MST1–LATS1 signaling is upregulated in spinal motor neurons of [ALS](/diseases/amyotrophic-lateral-sclerosis) patients and SOD1-G93A mice. YAP phosphorylation (inactivation) by LATS1 in motor neurons correlates with disease progression and motor neuron loss. YAP overexpression or LATS1 knockdown in motor neuron cultures protects against [TDP-43](/genes/tardbp) and [FUS](/entities/fus) aggregate toxicity, at least in part by sustaining [TEAD4](/genes/tead4)-dependent transcription of mitochondrial biogenesis genes.

Brain Tumors

LATS1 functions as a tumor suppressor in multiple brain cancers. Promoter hypermethylation silences LATS1 in ~40% of glioblastomas and ~30% of meningiomas. Loss of LATS1 de-represses YAP/TAZ, driving TEAD-dependent transcription of proliferative (CCND1, MYC), anti-apoptotic (BIRC5, BCL2L1), and stem cell (SOX2, OCT4) genes. LATS1 loss cooperates with [NF2](/genes/nf2) mutation in meningioma development.

Common Variants

| Variant | Type | Association | Reference |
|---------|------|-------------|-----------|
| rs9392510 | Intronic | Nominal association with hippocampal volume | [Bis et al., 2012](https://doi.org/10.1038/ng.2250) |
| Promoter hypermethylation | Epigenetic | LATS1 silencing in glioblastoma (~40%) | [Jiang et al., 2006](https://doi.org/10.1038/sj.onc.1209591) |
| c.2834C>T (P945L) | Missense | Reduced kinase activity, meningioma | [Petrilli & Bhatt, 2016](https://doi.org/10.1002/dvg.22945) |
| Loss of heterozygosity (6q25) | Deletion | Glioma, astrocytoma progression | [Kosikova et al., 2020](https://doi.org/10.3390/ijms21228984) |

Therapeutic Implications

LATS1 Inhibitors for Neurodegeneration

• TRULI (LATS1/2 inhibitor): A recently identified small molecule that directly inhibits LATS1/2 kinase activity, restoring YAP nuclear localization. Promotes retinal ganglion cell regeneration and Müller glia reprogramming in retinal degeneration models; brain applications are under investigation
• Verteporfin: Disrupts YAP–TEAD interaction (downstream of LATS1); used as a research tool but has poor brain penetration
• Challenge: LATS1 inhibition liberates YAP/TAZ, which have oncogenic potential. Tissue-specific or transient LATS1 inhibition strategies (AAV-shRNA, degradable small molecules) are needed to avoid tumor risk

LATS1 Activation for Cancer

• Restoring LATS1 expression via epigenetic drugs (DNMT inhibitors, [HDAC](/genes/hdac1) inhibitors) is an anti-cancer strategy in glioblastoma
• MST1/2 activators (e.g., C19) indirectly activate LATS1 and suppress YAP-driven tumor growth

Hippo Pathway Modulation

Expression Profile

| Brain Region | Expression Level | Cell Types |
|---|---|---|
| Hippocampus (CA1, DG) | High | Pyramidal neurons, granule cells, astrocytes |
| Cerebral cortex | Moderate-High | Pyramidal neurons, interneurons |
| Cerebellum | Moderate | Purkinje cells, granule neurons |
| Substantia nigra | Moderate | Dopaminergic neurons |
| Spinal cord (ventral horn) | Moderate | Motor neurons |
| SVZ/SGZ | Moderate | Neural stem/progenitor cells |

See Also

• [YAP1](/genes/yap1) — YAP transcriptional co-activator, direct LATS1 substrate
• [WWTR1](/genes/wwtr1) — TAZ transcriptional co-activator, direct LATS1 substrate
• [MST1](/genes/mst1) — MST1/STK4 kinase, upstream LATS1 activator
• [STK3](/genes/stk3) — MST2 kinase, upstream LATS1 activator
• [NF2](/genes/nf2) — Merlin, upstream Hippo pathway activator
• [LATS2](/genes/lats2) — LATS1 paralog
• [PRKAA1](/genes/prkaa1) — AMPKα1, LATS1 activator under energy stress
• [Hippo Signaling Pathway](/mechanisms/hippo-signaling-pathway)

External Links

• [NCBI Gene: LATS1](https://www.ncbi.nlm.nih.gov/gene/9113)
• [UniProt: O95835](https://www.uniprot.org/uniprot/O95835)
• [GeneCards: LATS1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=LATS1)
• [OMIM: 603473](https://omim.org/entry/603473)
• [Allen Brain Atlas: LATS1](https://human.brain-map.org/)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving LATS1 — Large Tumor Suppressor Kinase 1, Hippo Pathway discovered through SciDEX knowledge graph analysis: