| Full Name | Large Tumor Suppressor Kinase 2 |
| Gene Symbol | LATS2 |
| Chromosomal Location | 13q12.11 |
| NCBI Gene ID | [26524](https://www.ncbi.nlm.nih.gov/gene/26524) |
| OMIM | [604861](https://omim.org/entry/604861) |
| Ensembl | [ENSG00000150457](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000150457) |
| UniProt (Protein) | [Q9NRM7 (LATS2)](https://www.uniprot.org/uniprot/Q9NRM7) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), Glioblastoma, [Huntington's Disease](/diseases/huntingtons-disease) |
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, functioning in parallel with its paralog LATS1 to phosphorylate and inhibit the transcriptional co-activators YAP1 and TAZ/WWTR1. LATS2 acts as a critical regulator of organ size control, cell proliferation, 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.
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 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 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, hippocampal pyramidal cells, Purkinje cells, astrocytes, and microglia. The Allen Brain Atlas shows moderate expression across cortical regions with enrichment in the hippocampus, cerebellum, and amygdala.
LATS2 is an AGC family serine/threonine kinase with the following domain architecture:
The LATS2 activation cascade proceeds as follows:
LATS2 also has Hippo pathway-independent functions:
In AD, LATS2 expression and activity are elevated in reactive 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/PS1 mice, conditional LATS2 knockdown in 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.
LATS2 mediates dopaminergic neuron vulnerability in PD. α-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.
In ALS, 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 aggregation triggers MST1-LATS2 axis activation through cytoplasmic stress granule-dependent mechanisms.
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.
| 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 |