GO:0035332 positive regulation of hippo signaling: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0035332 describes any process that activates or increases the frequency, rate or extent of hippo signaling, a conserved kinase cascade that controls cell proliferation, apoptosis and organ size [1,2,3].
• Positive regulation of hippo signaling often means enhanced phosphorylation of YAP/TAZ, leading to their cytoplasmic retention or degradation and reduced transcriptional output [2,3,6].
• Key upstream activators include cell polarity proteins, junctional complexes, and metabolic or stress signals that converge on MST1/2 and LATS1/2 kinases [3,5,8].
• Dysregulation of positive regulation of hippo signaling is implicated in cancers such as gastric, liver, and triple-negative breast cancer, as well as neurodegeneration and ovarian insufficiency [1,2,3,5,6,7].
• Experimental models for studying this process include CRISPR knockout, point mutation, knock-in, and overexpression cell lines, combined with phospho-protein analysis and transcriptomics [2,4,8].
• EDITGENE provides custom CRISPR services to dissect positive regulation of hippo signaling, from gene knockout to library screening and bioinformatics.
Description
The Hippo signaling pathway is an evolutionarily conserved kinase cascade that restricts organ size by inhibiting the transcriptional co-activators YAP and TAZ [1,3]. GO:0035332, positive regulation of hippo signaling, refers to any process that activates or increases the frequency, rate or extent of this cascade [1,2]. This term is critical for understanding how cells integrate mechanical, metabolic, and chemical cues to control proliferation and apoptosis [3,5,8]. Research has shown that positive regulation of hippo signaling can be driven by diverse inputs, including cell-cell adhesion, G-protein coupled receptors, and metabolic enzymes [3,5,8]. For example, the alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase that promotes YAP signaling, indirectly modulating Hippo output in gastric cancer. Similarly, the oxytocin receptor regulates the Hippo/YAP axis to drive hepatocarcinogenesis. These findings highlight the complexity of positive regulation and its relevance to human disease. Understanding GO:0035332 is essential for researchers aiming to manipulate the pathway for therapeutic benefit. This article synthesizes verified literature to describe the mechanisms, key genes, disease associations, and experimental methods for studying positive regulation of hippo signaling.
positive regulation of hippo signaling At A Glance
| GO ID | GO:0035332 |
|---|---|
| GO term | positive regulation of hippo signaling |
| Ontology | biological_process |
| Synonym | positive regulation of hippo signaling cascade; positive regulation of hippo signaling pathway; positive regulation of hippo signalling cascade |
| Major function | Activates or increases the Hippo kinase cascade, leading to YAP/TAZ inhibition and altered cell proliferation, apoptosis, and organ size [1,2,3] |
| Upstream regulators | Cell polarity proteins, junctional complexes, GPCRs, metabolic enzymes, and mechanical cues [3,5,8] |
| Key downstream effectors | YAP/TAZ transcriptional co-activators, TEAD transcription factors [2,3,6] |
| Disease relevance | Cancer (gastric, liver, breast), neurodegeneration, ovarian insufficiency [1,2,3,5,6,7] |
What Is GO:0035332?
Positive regulation of hippo signaling (GO:0035332) encompasses any biological process that activates or increases the frequency, rate or extent of the Hippo signaling cascade. In practice, this often involves enhanced kinase activity of MST1/2 and LATS1/2, leading to increased phosphorylation of YAP/TAZ and their subsequent cytoplasmic sequestration or degradation [2,3,6].
Why Is positive regulation of hippo signaling Important in Cell Biology?
Positive regulation of hippo signaling is a central mechanism controlling organ size, tissue homeostasis, and regeneration. Its dysregulation contributes to cancer progression, fibrosis, and degenerative diseases, making it a prime target for therapeutic intervention [1,2,3,5,6,7,8].
• Controls cell proliferation and apoptosis through YAP/TAZ inhibition [2,3,6].
• Regulates organ size and tissue homeostasis [1,3].
• Implicated in gastric cancer tumorigenesis via CXCR7 and AARS1 [2,3].
• Drives hepatocarcinogenesis through oxytocin receptor signaling.
• Modulates triple-negative breast cancer progression via RNF187.
• Linked to amyloid-beta-mediated neurodegeneration through JNK crosstalk.
• Affects ovarian function and premature ovarian insufficiency.
• Influences arterial stiffening via DDR1 phase separation.
• Provides targets for CRISPR-based functional screens [2,4,8].
• Enables development of small molecule modulators for cancer therapy [1,5].
What Happens During positive regulation of hippo signaling?
Upstream signal integration
In simple terms: Cells sense external and internal cues that tell them to activate the Hippo pathway.
Positive regulation of hippo signaling begins with diverse upstream inputs, including cell-cell adhesion, mechanical forces, G-protein coupled receptor (GPCR) signaling, and metabolic stress [3,5,8]. For instance, the oxytocin receptor regulates the Hippo/YAP axis in hepatocarcinogenesis, while DDR1 liquid-liquid phase separation counteracts the Hippo pathway to orchestrate arterial stiffening. These signals converge on the core kinase cassette.
Core kinase cascade activation
In simple terms: A series of kinases turn each other on, ultimately adding phosphate groups to YAP/TAZ.
The core Hippo kinase cascade involves MST1/2 (STK4/3) and LATS1/2. Positive regulation increases their activity, often through phosphorylation and scaffolding by proteins like NF2 and WW45 [1,3]. Activated LATS1/2 then phosphorylate YAP and TAZ at multiple sites, promoting their cytoplasmic retention or ubiquitin-mediated degradation [2,6].
YAP/TAZ phosphorylation and inactivation
In simple terms: Phosphorylation tags YAP/TAZ for removal from the nucleus, stopping them from turning on growth genes.
Phosphorylated YAP/TAZ are recognized by 14-3-3 proteins and sequestered in the cytoplasm, or targeted for degradation by the ubiquitin-proteasome system [2,6]. This reduces their interaction with TEAD transcription factors, leading to decreased expression of proliferative and anti-apoptotic genes [1,3].
Crosstalk with other signaling pathways
In simple terms: The Hippo pathway talks to other communication lines, like JNK and WNT, to fine-tune its effects.
Positive regulation of hippo signaling can be modulated by crosstalk with JNK and WNT pathways. For example, a positive feedback loop between Hippo and JNK signaling regulates amyloid-beta-mediated neurodegeneration. Additionally, FZD10 upregulation in liver cancer stem cells involves WNT/β-catenin and Hippo signaling pathways.
Transcriptional and phenotypic outcomes
In simple terms: The final result is changes in which genes are turned on or off, affecting cell growth and survival.
Enhanced Hippo signaling leads to reduced YAP/TAZ target gene expression, resulting in decreased cell proliferation, increased apoptosis, and altered differentiation [2,3,5]. These phenotypic changes are critical for tumor suppression and tissue homeostasis [1,6].
Key Genes Involved in GO:0035332 positive regulation of hippo signaling
The following genes and proteins are central to positive regulation of hippo signaling, as supported by verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| STK3/4 (MST1/2) | Core kinases that phosphorylate LATS1/2 | Central to pathway activation; targets for knockout studies [1,3] |
| LATS1/2 | Phosphorylate YAP/TAZ | Key effectors; mutations affect cancer progression [2,6] |
| YAP1 | Transcriptional co-activator; inhibited by Hippo signaling | Oncogene; overexpression models [2,3,5] |
| WWTR1 (TAZ) | Paralog of YAP; regulated by Hippo | Implicated in breast cancer and metastasis |
| NF2 | Scaffold protein that activates MST1/2 | Tumor suppressor; knockout models |
| CXCR7 | GPCR that regulates Hippo/YAP axis | Gastric cancer tumorigenesis |
| AARS1 | Moonlighting lactyltransferase promoting YAP | Gastric cancer; metabolic regulation |
| OXTR | Oxytocin receptor; regulates Hippo/YAP | Hepatocarcinogenesis |
| RNF187 | Ubiquitin ligase regulating Hippo signaling | Triple negative breast cancer |
| DDR1 | Receptor tyrosine kinase; phase separation counteracts Hippo | Arterial stiffening |
| FZD10 | WNT receptor; crosstalk with Hippo | Liver cancer stem cells; lenvatinib resistance |
| TEAD1-4 | Transcription factors binding YAP/TAZ | Downstream effectors; drug targets [2,3] |
| JNK1/2 | Stress kinases crosstalking with Hippo | Neurodegeneration |
| MST1 | Pro-apoptotic kinase in Hippo pathway | Ovarian insufficiency |
| LATS1 | Tumor suppressor kinase | Breast cancer |
| CTGF | YAP/TAZ target gene | Readout of Hippo activity |
| CYR61 | YAP/TAZ target gene | Readout of Hippo activity |
| AMOT | Junctional protein regulating Hippo | Cell polarity studies |
How Is positive regulation of hippo signaling Regulated?
Positive regulation of hippo signaling is itself tightly regulated by upstream inputs such as cell density, mechanical forces, and metabolic cues [3,5,8]. For example, the oxytocin receptor activates the Hippo/YAP axis in liver cancer, while DDR1 phase separation counteracts the pathway in arterial stiffening. Additionally, AARS1-mediated lactylation promotes YAP signaling, indirectly modulating Hippo output. These regulatory mechanisms ensure context-dependent control of YAP/TAZ activity.
positive regulation of hippo signaling and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CXCR7 | Gastric cancer | Knockout and overexpression in gastric cancer cell lines |
| AARS1 | Gastric cancer | Point mutation of lactyltransferase domain |
| OXTR | Hepatocarcinogenesis | Knockout in liver cancer cells |
| RNF187 | Triple negative breast cancer | Overexpression and knockout in breast cancer cells |
| DDR1 | Arterial stiffening | Knock-in of phase separation mutants |
Cancer
Dysregulation of positive regulation of hippo signaling is frequently observed in cancers. In gastric cancer, CXCR7 regulates the Hippo/YAP axis to promote tumorigenesis, and AARS1 promotes YAP signaling. In liver cancer, FZD10 upregulation involves WNT/β-catenin and Hippo pathways, contributing to lenvatinib resistance. Triple-negative breast cancer progression is regulated by the ubiquitin ligase RNF187. These findings underscore the therapeutic potential of targeting Hippo signaling in oncology.
Neurodegeneration
A positive feedback loop between Hippo and JNK signaling regulates amyloid-beta-mediated neurodegeneration. This crosstalk suggests that modulating positive regulation of hippo signaling could influence neuronal survival and disease progression.
Ovarian insufficiency
Human umbilical cord mesenchymal stem cell-derived exosomes improve ovarian function and proliferation in premature ovarian insufficiency by regulating the Hippo signaling pathway. This highlights a role for positive regulation of hippo signaling in reproductive biology.
Cardiovascular disease
Liquid-liquid phase separation of DDR1 counteracts the Hippo pathway to orchestrate arterial stiffening. This implicates positive regulation of hippo signaling in vascular remodeling and cardiovascular disease.
From positive regulation of hippo signaling-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X activate Hippo signaling? | CRISPR knockout of gene X in HEK293 or cancer cells [2,3] |
| Does mutation Y affect YAP phosphorylation? | Point mutation knock-in of YAP/TAZ [2,6] |
| Does gene X interact with LATS1? | Tagged knock-in (e.g., FLAG-LATS1) for co-IP |
| Does overexpression of gene X inhibit proliferation? | Doxycycline-inducible overexpression |
| Which genes regulate Hippo signaling? | CRISPR library screening with YAP/TAZ reporter [2,4] |
| Does gene X affect Hippo in vivo? | Xenograft or organoid models [3,8] |
How to Study the positive regulation of hippo signaling Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Western blot | Phospho-YAP/TAZ and LATS1 levels | Assess pathway activation [2,3] |
| Luciferase reporter | TEAD transcriptional activity | Screen for regulators [1,3] |
| CRISPR screen | Gene essentiality or reporter activation | Identify novel Hippo regulators [2,4] |
| Co-immunoprecipitation | Protein-protein interactions | Study LATS1-YAP binding |
| Immunofluorescence | Subcellular localization of YAP/TAZ | Determine cytoplasmic retention [3,8] |
| RNA-seq | Transcriptional changes | Identify YAP/TAZ target genes [1,5] |
| Proteomics | Global protein expression and modifications | Discover lactylation of YAP |
| Organoid culture | 3D tissue-like growth | Model cancer and drug response [3,8] |
Phospho-protein analysis
Western blotting for phosphorylated YAP (Ser127) and LATS1 (Thr1079) is a standard method to assess positive regulation of hippo signaling [2,3,6]. This provides direct readout of kinase activity.
Transcriptional reporter assays
Luciferase reporters driven by TEAD-binding elements (e.g., 8xGTIIC-luciferase) measure YAP/TAZ transcriptional activity, reflecting Hippo pathway output [1,3].
CRISPR screening
Genome-wide CRISPR knockout or activation screens coupled with YAP/TAZ reporters can identify novel regulators of positive regulation of hippo signaling [2,4].
Imaging and phase separation
Fluorescence microscopy and FRAP can visualize YAP/TAZ localization and DDR1 phase separation, providing spatial insights into Hippo regulation.
How CRISPR Can Be Used to Study GO:0035332 positive regulation of hippo signaling
Knockout
CRISPR knockout of genes such as CXCR7, AARS1, or OXTR can determine their necessity for positive regulation of hippo signaling. For example, knockout of CXCR7 in gastric cancer cells reduces YAP activity and tumorigenesis.
Point Mutation
Introducing point mutations in YAP (e.g., S127A) prevents its phosphorylation and inactivation, thereby blocking positive regulation of hippo signaling. This is useful to study downstream effects [2,6].
Knock-in
Tagged knock-in of LATS1 or YAP (e.g., GFP or FLAG) allows real-time tracking of protein localization and interactions, providing mechanistic insights into positive regulation.
Overexpression
Overexpression of upstream activators like MST1 or LATS1 can enhance positive regulation of hippo signaling, leading to reduced cell proliferation. This approach is valuable for validating tumor suppressor functions.
How EDITGENE Supports positive regulation of hippo signaling Research
Researchers studying positive regulation of hippo signaling-related genes often need to determine whether a candidate gene is causally involved in pathway activation or if it merely correlates with changes in YAP/TAZ activity. EDITGENE provides a comprehensive suite of CRISPR services to address these questions with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of hippo signaling research.
Frequently Asked Questions About positive regulation of hippo signaling
What is positive regulation of hippo signaling?
Positive regulation of hippo signaling (GO:0035332) is any process that activates or increases the Hippo kinase cascade, leading to YAP/TAZ inhibition [1,2,3].
What genes are involved in positive regulation of hippo signaling?
Key genes include STK3/4 (MST1/2), LATS1/2, NF2, CXCR7, AARS1, OXTR, RNF187, and DDR1 [1,2,3,5,6,8].
How does positive regulation of hippo signaling affect cancer?
It can suppress tumor growth by inhibiting YAP/TAZ, but dysregulation contributes to gastric, liver, and breast cancers [1,2,3,5,6].
What are the downstream effects of positive regulation of hippo signaling?
Increased phosphorylation and inactivation of YAP/TAZ, reduced TEAD-mediated transcription, and decreased cell proliferation [2,3,6].
Which diseases are linked to positive regulation of hippo signaling?
Cancer, neurodegeneration, ovarian insufficiency, and cardiovascular disease [1,2,3,4,5,6,7,8].
How can I study positive regulation of hippo signaling in the lab?
Use phospho-protein analysis, luciferase reporters, CRISPR screens, and imaging techniques [1,2,3,4,8].
What CRISPR models are available for Hippo signaling research?
Knockout, point mutation, knock-in, and overexpression cell lines, as well as library screening [2,3,4,5,8].
What is the role of YAP in positive regulation of hippo signaling?
YAP is a transcriptional co-activator that is inhibited by Hippo signaling; its phosphorylation leads to cytoplasmic retention [2,3,6].
How does AARS1 regulate Hippo signaling?
AARS1 moonlights as a lactyltransferase that promotes YAP signaling in gastric cancer.
What methods measure Hippo pathway activity?
Western blot for phospho-YAP, luciferase reporters, RNA-seq, and immunofluorescence [1,2,3,5,8].
Conclusion
Positive regulation of hippo signaling (GO:0035332) is a fundamental process controlling cell growth and organ size, with broad implications for cancer, neurodegeneration, and regenerative medicine. Understanding its molecular players and regulatory mechanisms is essential for developing targeted therapies. EDITGENE offers advanced CRISPR solutions to accelerate discoveries in this field.
References
- 1. Wang J et al.. 2023. N6-Methyladenosine-Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance Through WNT/β-Catenin and Hippo Signaling Pathways.. Gastroenterology 164(6):990-1005 PMID: 36764493
- 2. Ju J et al.. 2024. The alanyl-tRNA synthetase AARS1 moonlights as a lactyltransferase to promote YAP signaling in gastric cancer.. J Clin Invest 134(10) PMID: 38512451
- 3. Wang T et al.. 2023. Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer.. J Exp Clin Cancer Res 42(1):297 PMID: 37950281
- 4. Li Z et al.. 2021. Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Improve Ovarian Function and Proliferation of Premature Ovarian Insufficiency by Regulating the Hippo Signaling Pathway.. Front Endocrinol (Lausanne) 12:711902 PMID: 34456868
- 5. Yang H et al.. 2025. Oxytocin Receptor Regulates the Hippo/YAP Axis to Drive Hepatocarcinogenesis.. Cancer Res 85(19):3752-3770 PMID: 40742309
- 6. Wang Z et al.. 2020. Regulation of Hippo signaling and triple negative breast cancer progression by an ubiquitin ligase RNF187.. Oncogenesis 9(3):36 PMID: 32198343
- 7. Irwin M et al.. 2020. A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration.. Front Cell Dev Biol 8:117 PMID: 32232042
- 8. Liu J et al.. 2023. Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening.. Circ Res 132(1):87-105 PMID: 36475898
