| Full Name | Large Tumor Suppressor Kinase 1 |
| Gene Symbol | LATS1 |
| Chromosomal Location | 6q25.1 |
| NCBI Gene ID | [9113](https://www.ncbi.nlm.nih.gov/gene/9113) |
| OMIM | [603473](https://omim.org/entry/603473) |
| Ensembl | [ENSG00000131023](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000131023) |
| UniProt (Protein) | [O95835 (LATS1)](https://www.uniprot.org/uniprot/O95835) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), Glioblastoma, Meningioma |
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, and stem cell self-renewal. LATS1, together with its paralog LATS2, directly phosphorylates and inactivates the transcriptional co-activators YAP1 and TAZ (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, Parkinson's disease, and brain tumors, positioning LATS1 as a key node connecting developmental growth control to neurodegenerative pathology.
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 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, astrocytes, microglia, and oligodendrocytes. The Allen Brain Atlas shows moderate-to-high expression across the hippocampus, cerebral cortex, and cerebellum, with enrichment in the CA1 region and dentate gyrus.
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/MST2 (STK3) phosphorylate the LATS1 hydrophobic motif (T1079), followed by LATS1 autophosphorylation of its activation loop (S909).
The Hippo signaling cascade proceeds as follows:
Beyond YAP/TAZ, LATS1 phosphorylates additional substrates with neurological relevance:
LATS1 activity is modulated by diverse signals relevant to neurodegeneration:
LATS1 plays multiple roles in CNS development:
Hippo pathway activity through LATS1 is significantly altered in AD. Postmortem AD brain tissue shows decreased LATS1 phosphorylation (inactive kinase) and corresponding nuclear YAP accumulation in hippocampal neurons and reactive 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 and anti-apoptotic BCL-XL, and YAP degradation by excessive LATS1 activity may deprive neurons of survival signals. This dual role complicates therapeutic targeting.
Tau pathology directly impairs Hippo signaling: hyperphosphorylated tau disrupts the MST1–SAV1 complex required for LATS1 activation, while Aβ 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).
In PD models, LATS1 is activated by α-synuclein-induced oxidative stress, leading to YAP phosphorylation and cytoplasmic sequestration in dopaminergic neurons. LATS1-mediated YAP inactivation reduces expression of survival genes including 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/Parkin-mediated mitophagy: LATS1 phosphorylation of Beclin-1 promotes the autophagy–mitophagy switch, and LATS1 deficiency impairs selective mitochondrial clearance.
MST1–LATS1 signaling is upregulated in spinal motor neurons of ALS 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 and FUS aggregate toxicity, at least in part by sustaining TEAD4-dependent transcription of mitochondrial biogenesis genes.
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 mutation in meningioma development.
| Variant | Type | Association | Reference |
|---|---|---|---|
| rs9392510 | Intronic | Nominal association with hippocampal volume | Bis et al., 2012 |
| Promoter hypermethylation | Epigenetic | LATS1 silencing in glioblastoma (~40%) | Jiang et al., 2006 |
| c.2834C>T (P945L) | Missense | Reduced kinase activity, meningioma | Petrilli & Bhatt, 2016 |
| Loss of heterozygosity (6q25) | Deletion | Glioma, astrocytoma progression | Kosikova et al., 2020 |
Targeting the Hippo pathway at multiple nodes — combining LATS1 modulation with MST1/MST2 regulators, 14-3-3 protein modulators, or TEAD inhibitors — may achieve the desired balance between neuroprotection and tumor suppression.
| 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 |