The Hippo signaling pathway is a highly conserved kinase cascade that regulates cell proliferation, apoptosis, and tissue homeostasis. In the context of 4R-tauopathies—including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Argyrophilic Grain Disease (AGD), Globular Glial Tauopathy (GGT), and Frontotemporal Dementia with Parkinsonism-17 (FTDP-17)—the Hippo pathway emerges as a critical nexus linking tau pathology to neuronal survival and dysfunction.
This page provides a comprehensive cross-disease comparison of Hippo/YAP/TAZ signaling across these disorders, examining the molecular mechanisms by which 4-repeat tau (4R-tau) pathology intersects with this key developmental and stress-response pathway.
The Hippo pathway consists of a serial kinase cascade that ultimately controls the subcellular localization and activity of YAP (Yes-Associated Protein) and TAZ (WWTR1):
flowchart TD
A["Cellular Stress"] --> B["MST1/2 Kinase"]
B --> C["SAV1 Scaffold"]
C --> D["LATS1/2 Kinase"]
D --> E["MOB1A/B"]
E --> F{"YAP/TAZ<br/>Phosphorylation"}
F -->|"Phosphorylated"| G["Cytoplasmic Retention"]
G --> H["Proteasomal Degradation"]
F -->|"Unphosphorylated"| I["Nuclear Translocation"]
I --> J["TEAD1-4 Binding"]
J --> K["Pro-Survival Gene Expression"]
K --> L["Neuronal Survival"]
H --> M["Reduced Neuroprotection"]
M --> N["Neurodegeneration"]
style A fill:#e3f2fd
style K fill:#c8e6c9
style N fill:#ffcdd2
| Component |
Gene |
Cellular Function |
4R-Tauopathy Relevance |
| MST1 |
MST1 |
Core kinase, stress sensor |
Hyperactivated by tau pathology, pro-apoptotic |
| MST2 |
MST2 |
Redundant kinase function |
Compensatory role in neuron survival |
| SAV1 |
SAV1 |
Scaffold protein |
Forms complex with MST1/2 |
| LATS1 |
LATS1 |
Kinase, phosphorylates YAP/TAZ |
Tumor suppressor function |
| LATS2 |
LATS2 |
Redundant kinase |
Ubiquitin-mediated degradation |
| MOB1A/B |
MOB1A |
Scaffold for LATS activation |
Essential for kinase cascade |
| YAP1 |
YAP1 |
Transcriptional co-activator |
Pro-survival when nuclear |
| TAZ |
WWTR1 |
Transcriptional co-activator |
Reduced in tauopathy brains |
| TEAD1-4 |
TEAD1 |
Partner transcription factors |
YAP/TAZ nuclear partners |
¶ Tau Pathology and Hippo Pathway Dysregulation
Emerging evidence demonstrates that tau pathology directly impacts Hippo pathway signaling through multiple mechanisms:
- MST1 kinase activation: Pathological tau aggregates activate MST1 kinase, triggering the downstream kinase cascade
- YAP/TAZ cytoplasmic sequestration: Phosphorylated YAP/TAZ are trapped in the cytoplasm, preventing pro-survival transcription
- TEAD target gene downregulation: Reduced nuclear YAP/TAZ leads to decreased expression of TEAD-dependent survival genes
- Proteasomal dysfunction: Tau pathology impairs proteasome function, affecting YAP/TAZ degradation kinetics
4R-tau (containing 4 microtubule-binding repeats) exhibits distinct pathological characteristics compared to 3R-tau:
- Filament structures: Cryo-EM studies reveal distinct filament architectures in PSP and CBD compared to AD
- Aggregation propensity: 4R-tau shows faster aggregation kinetics
- Cellular distribution: 4R-tau exhibits different cellular and regional distribution patterns
- Post-translational modifications: Differential phosphorylation, acetylation, and truncation patterns
PSP shows prominent Hippo pathway dysregulation:
- MST1 hyperactivation: Increased MST1 phosphorylation in substantia nigra and basal ganglia
- YAP nuclear exclusion: Reduced nuclear YAP in affected neurons
- TEAD target downregulation: Decreased expression of pro-survival genes
- Substrate specificity: 4R-tau filaments show unique conformational features
CBD exhibits distinct Hippo pathway alterations:
- Cortical neuron vulnerability: YAP dysregulation particularly pronounced in pyramidal neurons
- Astrocytic involvement: Astrocytic plaques may affect local Hippo signaling
- Cell-type specific patterns: Differential effects on neurons vs. glia
AGD shows characteristic Hippo pathway changes:
- Dendritic grain pathology: Argyrophilic grains affect neuronal processes
- Incidental vs. comorbid: Distinction between pure AGD and AGD with other pathologies
- Aging association: Strong correlation with advancing age
GGT demonstrates unique Hippo pathway involvement:
- Glial pathology: Globular tau inclusions in astrocytes and oligodendrocytes
- White matter involvement: Distinct from other 4R-tauopathies
- Stereotyped progression: Predictable spread pattern
Genetic 4R-tauopathies show specific patterns:
- MAPT mutations: Over 40 mutations in MAPT gene cause FTDP-17
- Mutation-specific effects: Different mutations show varying 4R-tau dominance
- YAP/TAZ dysregulation: Direct effects on Hippo pathway gene expression
flowchart LR
subgraph PSP
A1["4R-tau filaments"] --> B1["MST1 activation"]
B1 --> C1["YAP nuclear exclusion"]
C1 --> D1["Nigral neuron loss"]
end
subgraph CBD
A2["4R-tau astrocytic plaques"] --> B2["Cortical MST1"]
B2 --> C2["YAP dysregulation"]
C2 --> D2["Pyramidal neuron loss"]
end
subgraph AGD
A3["Argyrophilic grains"] --> B3["Dendritic MST1"]
B3 --> C3["YAP redistribution"]
C3 --> D3["Dendritic degeneration"]
end
subgraph GGT
A4["Globular glial tau"] --> B4["Glial MST1"]
B4 --> C4["Astrocyte YAP"]
C4 --> D4["Glial dysfunction"]
end
subgraph FTDP-17
A5["MAPT mutation"] --> B5["Direct YAP/TAZ effects"]
B5 --> C5["Transcriptional dysregulation"]
C5 --> D5["Variable neuron loss"]
end
style A1 fill:#fff3e0
style A2 fill:#e8f5e9
style A3 fill:#e3f2fd
style A4 fill:#fce4ec
style A5 fill:#f3e5f5
Pathological tau activates MST1 kinase through multiple pathways:
- Direct interaction: Tau can bind MST1 and activate its kinase domain
- Oxidative stress: Tau pathology generates ROS, which activates MST1
- Calcium dysregulation: Tau-mediated calcium abnormalities activate calcium-dependent kinases
- Mitochondrial dysfunction: Tau impairs mitochondrial function, triggering stress response
Tau pathology impairs YAP/TAZ nuclear translocation:
- Phosphorylation-dependent retention: Increased LATS1/2 activity phosphorylates YAP at Ser127
- 14-3-3 binding: Phosphorylated YAP binds 14-3-3 proteins, sequestering in cytoplasm
- Proteasomal degradation: Cytoplasmic YAP undergoes ubiquitination and degradation
- Direct tau-YAP interaction: Tau can directly bind YAP, affecting its function
TEAD-dependent transcription is downregulated in tauopathies:
- Reduced nuclear coactivators: Less YAP/TAZ available for TEAD binding
- TEAD protein levels: Altered TEAD expression in affected brain regions
- Target gene expression: Reduced expression of pro-survival genes
The Hippo pathway intersects extensively with Wnt signaling:
flowchart TD
subgraph Wnt Pathway
A["Wnt ligand"] --> B["β-catenin"]
B --> C["TCF/LEF Transcription"]
C --> D["Proliferation & Survival"]
end
subgraph Hippo Pathway
E["Stress signals"] --> F["MST1/2"]
F --> G["LATS1/2"]
G --> H["YAP/TAZ"]
H --> I["TEAD Transcription"]
I --> J["Pro-survival genes"]
end
D -.->|Crosstalk| J
J -.->|Feedback| D
B <-->|"β-catenin-YAP"| H
Key crosstalk points:
- β-catenin-YAP interaction: β-catenin can bind YAP, affecting both pathways
- Target gene overlap: Some genes regulated by both pathways
- Therapeutic implications: Dual targeting may show synergy
The Hippo pathway intersects with mTOR signaling:
- mTOR regulates LATS1/2: Active mTOR inhibits LATS1/2, promoting YAP nuclear localization
- YAP regulates mTOR: YAP can influence mTORC1 activity
- Therapeutic targeting: mTOR inhibitors affect Hippo pathway activity
YAP/TAZ regulate autophagic genes:
- TFEB activation: YAP promotes TFEB nuclear translocation
- Lysosomal function: Enhanced autolysosome formation
- Tau clearance: Improved autophagy of pathological tau
Recent research reveals a critical connection between Hippo signaling and ferroptosis:
- MST1 promotes ferroptosis: Activated MST1 enhances lipid peroxidation
- YAP protects against ferroptosis: Nuclear YAP promotes antioxidant gene expression
- Lats1/2 ablation paradoxically protective: Loss of Lats1/2 increases neuronal resilience against ferroptosis through unphosphorylated YAP
| Target |
Approach |
Development Status |
Examples |
| MST1/2 |
Inhibitors |
Preclinical |
Xmu-mp-1, Verteporfin |
| YAP/TAZ |
Activators |
Preclinical |
Small molecule activators |
| TEAD |
Agonists |
Early research |
Peptide agonists |
| LATS1/2 |
Activators |
Early research |
Upstream kinase activators |
- MST1 inhibitors: Block pro-apoptotic signaling
- YAP stabilization: Promote nuclear localization
- TEAD agonists: Enhance pro-survival transcription
- Combination approaches: Target multiple pathway nodes
| Feature |
PSP |
CBD |
AGD |
GGT |
FTDP-17 |
| MST1 activation |
+++ |
++ |
+ |
++ |
++ |
| YAP nuclear exclusion |
+++ |
++ |
+ |
++ |
++ |
| TEAD downregulation |
+++ |
++ |
+ |
++ |
++ |
| 4R-tau dominance |
+++ |
+++ |
+++ |
+++ |
+++ |
| Neuron loss pattern |
Nigral |
Cortical |
Limbic |
Variable |
Variable |
| Astrocyte involvement |
Tufted |
Astrocytic |
Grains |
Globular |
Variable |