The Hippo signaling pathway is a cell-state sensing system centered on the MST/MAP4K-LATS kinase network, with YAP/TAZ-TEAD serving as its major transcriptional output. Unlike classical signaling pathways with fixed ligands and receptors, Hippo integrates multiple inputs, including cell contact, polarity, mechanical force, GPCRs, growth factors, and energy status, and regulates transcriptional programs related to cell proliferation, survival, tissue remodeling, and regeneration by controlling YAP/TAZ phosphorylation and nuclear translocation.

Keywords: Hippo signaling pathway; YAP; TAZ; TEAD; MST1/2; LATS1/2; mechanotransduction; targeting strategies

1 Regulatory Basis of the Hippo Signaling Pathway

1.1 Basic Concept of the Hippo Signaling Pathway

The Hippo signaling pathway does not have a unified “Hippo ligand” or “Hippo receptor.” Its essence is a signaling network that converts the extracellular environment and the cell’s own state into transcriptional responses. Information such as upstream cell contact, polarity, mechanical tension, receptor signaling, and metabolic status can converge on the MST/MAP4K-LATS kinase system. LATS1/2 controls the phosphorylation, protein stability, and nucleocytoplasmic distribution of YAP and TAZ, ultimately determining whether YAP/TAZ can form active transcriptional complexes with TEAD in the nucleus. In the classical regulatory mode, increased activity of the Hippo core kinases generally leads to inhibition of YAP/TAZ; conversely, nuclear activation of YAP/TAZ usually corresponds to reduced LATS-mediated inhibitory effects.

1.2 Core Components of the Hippo Signaling Pathway

(1) MST1/2-SAV1 Kinase Module

MST1 and MST2 are encoded by STK4 and STK3, respectively, and belong to the Ste20-like serine/threonine kinase family. They are important components of the classical Hippo core kinase network. SAV1, a WW-domain-containing scaffold protein, participates in MST1/2 complex assembly and promotes transmission of core kinase signaling at membrane-associated regions. Activated MST1/2 can phosphorylate MOB1 and promote phosphorylation of the LATS1/2 hydrophobic motif, allowing upstream inhibitory signals to continue toward YAP/TAZ.

(2) MAP4K-LATS Parallel Regulatory Module

LATS1/2 does not receive input exclusively from MST1/2. Members such as MAP4K1/2/3/5 and MAP4K4/6/7 can transmit signals to LATS1/2 independently of MST1/2, and some MAP4Ks can directly promote phosphorylation of the LATS hydrophobic motif. Therefore, the mammalian Hippo pathway is more accurately viewed as a network in which multiple upstream kinases converge on LATS1/2 rather than a strict single-line “MST1/2→LATS1/2” cascade. Functional redundancy exists between MST1/2 and MAP4Ks, which is also one reason why partial activity of the LATS-YAP axis may remain after MST1/2 function is reduced alone.

(3) LATS1/2-MOB1 Effector Module

LATS1 and LATS2 belong to the NDR family of serine/threonine kinases and are the core effector kinases that directly inhibit YAP/TAZ in the classical Hippo pathway. MST1/2 can promote phosphorylation of MOB1 at sites such as Thr12/Thr35 and enhance MOB1-LATS functional coupling, while also promoting phosphorylation of hydrophobic-motif sites such as LATS1 Thr1079 and LATS2 Thr1041. Subsequent autophosphorylation of the LATS activation loop further generates a catalytically active kinase. Activated LATS1/2 directly acts on YAP/TAZ, making LATS an important signaling convergence node between upstream state sensing and downstream transcriptional output.

(4) YAP and TAZ Transcriptional Coactivators

YAP (Yes-associated protein) and TAZ are the major downstream transcriptional coactivators of the Hippo pathway, with TAZ encoded by WWTR1. YAP/TAZ themselves lack typical DNA-binding domains and cannot independently recognize target genes. Their functions are mainly controlled by phosphorylation, protein stability, nucleocytoplasmic transport, and nuclear protein interactions. When YAP/TAZ are in the cytoplasm, their transcriptional functions are restricted; after entering the nucleus, they can form active complexes with DNA-binding transcription factors such as TEAD.

(5) TEAD1-4 Transcription Factors

TEAD1, TEAD2, TEAD3, and TEAD4 are the major DNA-binding partners of YAP/TAZ. TEAD recognizes chromatin regulatory regions, while YAP/TAZ provides transcriptional coactivation, together forming the major nuclear output of the Hippo pathway. CCN1/CYR61, CCN2/CTGF, and ANKRD1 are commonly used as indicators of YAP/TAZ-TEAD activity, whereas outputs such as AREG and AXL show more pronounced dependence on cell type and chromatin context.

1.3 Basic Signal Transduction Modes of Hippo Signaling

(1) Active State of the Hippo Core Kinases

When high cell density, intact cell junctions, or other growth-inhibitory upstream inputs predominate, the MST/MAP4K-LATS network is activated. LATS1/2 further phosphorylates sites such as YAP Ser127 and TAZ Ser89, creating 14-3-3 protein-binding sites, causing YAP/TAZ to be retained more in the cytoplasm and reducing nuclear entry. At this time, TEAD lacks the transcriptional coactivation function provided by YAP/TAZ, and transcriptional programs related to proliferation, survival, and tissue remodeling are restricted.

(2) Phosphorylation-Dependent Degradation of YAP

LATS can further restrict YAP at the level of protein stability. After YAP Ser381 is phosphorylated by LATS, CK1δ/ε can further phosphorylate adjacent sequences, forming a phosphodegron that can be recognized by the SCF-β-TrCP ubiquitin ligase complex, followed by ubiquitination and proteasomal degradation. Therefore, the classical Hippo core kinases can simultaneously reduce effective YAP levels through cytoplasmic retention and protein degradation.

(3) Low-Activity State of the Hippo Core Kinases

When LATS1/2 activity decreases, inhibitory phosphorylation of YAP/TAZ is reduced, and YAP/TAZ accumulates in the nucleus. Nuclear YAP/TAZ binds TEAD1-4 and recruits Mediator, chromatin regulators, and other transcriptional components to enhance expression of genes related to the cell cycle, survival, extracellular matrix, and tissue remodeling. The core information flow of the Hippo pathway can therefore be summarized as: upstream state sensing → MST/MAP4K-LATS → YAP/TAZ localization and stability → TEAD transcriptional output.

Table 1 Two Typical States of Hippo Core Kinases and YAP/TAZ

1.4 Classical Hippo and Non-Classical YAP/TAZ Regulation

MST/MAP4K-LATS constitutes the classical regulatory axis of YAP/TAZ, but YAP/TAZ function is not completely determined by this kinase cascade. Actin cytoskeletal tension, nuclear-envelope mechanical state, nuclear-pore transport, and certain metabolic signals can directly or indirectly affect YAP/TAZ nuclear entry and transcriptional activity. Therefore, some models may show limited changes in p-YAP while nuclear YAP changes markedly. Hippo signaling research needs to distinguish LATS-dependent phosphorylation regulation from mechanotransduction and other regulatory mechanisms that are not completely LATS-dependent.

2 Upstream Regulatory Levels of the Hippo Pathway

2.1 Regulation by Cell Junctions and Polarity

(1) NF2 and KIBRA

NF2/Merlin and KIBRA (WWC1) participate in the spatial organization of Hippo core components near the cell membrane. NF2 can promote recruitment of LATS to membrane-associated regions, positioning it to receive upstream kinase regulation; KIBRA enhances the core kinase network by forming complexes with multiple Hippo components. Loss of NF2 function can weaken LATS-mediated restriction of YAP/TAZ, making NF2 abnormalities an important upstream mechanism of persistent YAP/TAZ activation in some contexts.

(2) AMOT Family

AMOT, AMOTL1, and AMOTL2 can bind the WW domains of YAP/TAZ through PPxY motifs and restrict YAP/TAZ entry into the nucleus. AMOT can also bind F-actin, and its phosphorylation status can regulate functional allocation between Actin binding and YAP/TAZ inhibition. Therefore, AMOT constitutes an important interface among cell junctions, the Actin cytoskeleton, and Hippo signaling.

(3) Polarity and Adhesion Complexes

Cell-junction and polarity components such as E-Cadherin, α-Catenin, CRUMBS, and SCRIBBLE can influence localization of the Hippo core kinases and YAP/TAZ. High cell density and intact epithelial junctions generally favor restriction of YAP/TAZ nuclear entry, whereas junction disruption, loss of polarity, and abnormal tissue architecture can weaken contact-dependent growth inhibition and enhance YAP/TAZ transcriptional programs.

2.2 GPCR-Mediated Hippo Regulation

(1) Gα12/13 and Gαq/11 Signaling

Some Gα12/13- or Gαq/11-coupled GPCRs can activate Rho GTPases, promote F-actin polymerization and actomyosin tension, and reduce LATS-mediated inhibition of YAP/TAZ, thereby increasing YAP/TAZ nuclear accumulation. Lipid mediators such as LPA and S1P can form GPCR-Rho-Actin-YAP/TAZ regulatory chains through their corresponding GPCRs, constituting an important connection between soluble factors and mechanotransduction.

(2) Gαs-cAMP-PKA Signaling

Gαs-coupled receptors can increase intracellular cAMP levels and activate PKA, promoting LATS-related YAP/TAZ inhibition in some cellular contexts. Different Gα subtypes may therefore exert opposite effects on YAP/TAZ, so GPCR-Hippo relationships should be analyzed according to the specific receptor, G-protein coupling mode, and cell type.

2.3 Mechanical Force and Cytoskeletal Regulation

(1) Matrix Stiffness and Integrin-FAK/Src Signaling

A stiff extracellular matrix can enhance Integrin clustering and focal-adhesion maturation and increase cell spreading, F-actin stress fibers, and contractile tension through FAK/Src-Rho signaling, generally promoting YAP/TAZ nuclear accumulation. A soft matrix reduces focal-adhesion maturation and cytoskeletal tension, causing YAP/TAZ to distribute more in the cytoplasm. YAP/TAZ therefore serves as an important effector node through which cells convert the physical properties of the extracellular matrix into nuclear transcriptional responses.

(2) Rho-ROCK-Actomyosin Axis

After RhoA activation, ROCK can promote myosin-light-chain-related phosphorylation and enhance Myosin II-mediated actomyosin contractility. Sustained mechanical tension can maintain a cytoskeletal state favorable for YAP/TAZ nuclear entry, whereas reducing ROCK, Myosin II, or F-actin function generally inhibits mechanically dependent YAP/TAZ activation. Therefore, the Rho-ROCK-actomyosin axis is an important intermediate module for transmitting mechanical information to the YAP/TAZ transcriptional output.

(3) Nuclear Mechanotransduction

Mechanical forces generated by the cytoskeleton can also be transmitted through the LINC complex to the nuclear skeleton and nuclear envelope, altering nuclear morphology, nuclear-envelope tension, and nuclear-pore state. Under conditions of higher mechanical tension, YAP nuclear-entry efficiency can increase. Therefore, some YAP mechanotransduction does not strictly require synchronous changes in MST-LATS phosphorylation. This mechanism further indicates that YAP/TAZ is not only a substrate of a kinase cascade but also a nuclear responder to cellular mechanical state.

2.4 Crosstalk Between RTK-PI3K and Hippo Signaling

Receptor tyrosine kinases such as EGFR can regulate YAP/TAZ through PI3K-PDK1, Rho, and cytoskeleton-associated networks. In some cellular models, enhanced EGFR-PI3K signaling can reduce restriction of YAP by Hippo core kinases and promote YAP nuclear accumulation and TEAD transcription, whereas PI3K inhibition can reduce the corresponding YAP output. Because PI3K also controls AKT, mTOR, and metabolic networks, this process represents signaling crosstalk between RTK-PI3K and Hippo rather than a single linear cascade.

2.5 Energy Status and Cellular Stress

(1) AMPK-YAP Metabolic Checkpoint

Energy stress such as glucose deprivation and ATP reduction can activate AMPK, causing cells to restrict energy-intensive growth and proliferation programs. AMPK can enhance YAP inhibition through mechanisms related to the Hippo core kinases and can also directly phosphorylate YAP. Changes at sites such as Ser94 can weaken the interaction between YAP and TEAD. Therefore, AMPK constitutes an important metabolic checkpoint between cellular energy status and YAP/TAZ transcriptional programs.

(2) Hypoxia and Other Stress

Hypoxia, oxidative stress, and endoplasmic reticulum stress can affect YAP/TAZ through multiple nodes, including HIF, AMPK, PI3K, ROS, and the cytoskeleton, and the direction of their effects shows clear dependence on cell type and stress stage. Some stress environments can promote YAP/TAZ-mediated adaptive transcription, while others inhibit YAP through energy restriction and core kinase activation. Therefore, these effects should be understood as integration of multiple stress networks with the Hippo transcriptional output.

2.6 Crosstalk With Wnt and TGF-β Signaling

The Hippo pathway has multilevel crosstalk with signaling pathways such as Wnt/β-Catenin and TGF-β/SMAD. YAP/TAZ can participate in β-Catenin-related regulation and can also form nuclear functional complexes with transcription factors such as SMAD, allowing Hippo signaling to further participate in stem-cell maintenance, EMT, lineage determination, and tissue remodeling. Therefore, YAP/TAZ is both a downstream effector of the Hippo core kinases and a transcriptional convergence node for multiple growth and developmental signals.

Figure 1. Upstream regulation, core kinase cascade, and YAP/TAZ–TEAD transcriptional output of the Hippo signaling pathway

3 Nuclear Transcriptional Regulation by YAP/TAZ-TEAD

3.1 TEAD-Dependent Transcriptional Programs

After entering the nucleus, YAP/TAZ mainly acquires DNA-binding ability through TEAD1-4 and recruits Mediator, chromatin regulators, and the basal transcription machinery at enhancer and promoter regions. CCN1/CYR61, CCN2/CTGF, and ANKRD1 are commonly used YAP/TAZ-TEAD transcriptional output indicators, whereas responses such as AXL, AREG, and MYC are dependent on tissue and chromatin context. Therefore, YAP/TAZ does not have a completely fixed target-gene spectrum; its functional output depends on TEAD occupancy, chromatin accessibility, and the cell-type-specific transcriptional environment.

3.2 TEAD Central Lipid Pocket and Palmitoylation

(1) TEAD Central Lipid Pocket

TEAD contains an N-terminal DNA-binding domain and a C-terminal YAP/TAZ-binding region, and a hydrophobic central lipid pocket is formed within the C-terminal region. This pocket can accommodate lipids and small-molecule ligands, providing TEAD with a relatively well-defined chemically bindable space among transcription factors and therefore forming an important structural basis for direct intervention in the terminal transcriptional output of the Hippo pathway.

(2) TEAD Palmitoylation

TEAD1-4 can undergo palmitoylation at conserved cysteine residues. After the lipid chain enters the central pocket, it participates in regulating TEAD conformation, stability, and transcriptional function. Chemical intervention targeting the central pocket or related lipid modifications can directly reduce TEAD transcription even when YAP remains in the nucleus. Therefore, TEAD targeting and promotion of YAP phosphorylation through LATS represent different levels of signal intervention.

3.3 Competitive Regulation by VGLL4

VGLL4 can compete with YAP for the TEAD-binding interface, thereby reducing YAP-TEAD-dependent transcription. This mechanism indicates that YAP/TAZ activity is not determined solely by nuclear localization; interactions between nuclear coactivators and competitive regulatory proteins also determine the final transcriptional output. Therefore, blocking YAP-TEAD interaction can inhibit the terminal Hippo signal without markedly changing total YAP levels or classical LATS phosphorylation status.

3.4 Non-TEAD Transcriptional Interactions and Higher-Order Transcriptional Organization

YAP/TAZ can also form functional complexes with DNA-binding transcription factors such as RUNX and SMAD, whereas YAP can additionally interact directly with p73 and regulate p73-dependent transcription and apoptotic responses, allowing Hippo signaling to participate in development, apoptosis, and TGF-β-related responses. Under specific cellular conditions, YAP/TAZ can also participate in the formation of nuclear transcriptional condensates and enrich TEAD, Mediator, and active chromatin components, indicating that their nuclear functions are simultaneously regulated by protein interactions, chromatin state, and spatial organization.

4 Major Biological Functions of the Hippo Signaling Pathway

4.1 Cell Proliferation and Organ Size Control

Activation of the Hippo core kinases can restrict the cell cycle and abnormal proliferation through inhibition of YAP/TAZ. When LATS-mediated inhibition is weakened, YAP/TAZ-TEAD can enhance transcription related to cell growth, survival, and biosynthesis. Cell density, tissue architecture, and mechanical tension can thereby feed back through the Hippo network to regulate cell number, coordinating tissue expansion with the physical scale of organs.

4.2 Stem Cell Fate and Tissue Regeneration

YAP/TAZ activity can regulate self-renewal of stem/progenitor cells, lineage selection, and proliferative responses after tissue injury. Moderate enhancement of YAP/TAZ during the injury phase favors cell proliferation and tissue repair, whereas sustained activation may hinder terminal differentiation or induce abnormal remodeling. Therefore, the role of the Hippo pathway in tissue regeneration shows marked dependence on time, dose, and tissue context.

4.3 Tumorigenesis, Invasion, and Treatment Resistance

Persistent activation of YAP/TAZ in tumors can be jointly driven by abnormalities in negative regulatory nodes such as NF2 and LATS, enhanced RTK/GPCR signaling, increased Rho-actin tension, or extracellular-matrix stiffening. Sustained YAP/TAZ-TEAD transcription can promote proliferation, survival, invasion, extracellular-matrix remodeling, and treatment adaptation and can form bypass compensation with pathways such as RAS-MAPK and PI3K-AKT. Therefore, nuclear YAP/TAZ activity can reflect a growth-promoting transcriptional state generated by convergence of multiple upstream abnormalities.

4.4 Immune and Tissue Microenvironment Remodeling

MST1/2, LATS1/2, and YAP/TAZ also participate in immune-cell function, inflammatory mediator expression, and intercellular communication. YAP/TAZ abnormalities not only alter the proliferative state of tumor or parenchymal cells themselves but can also remodel the tissue microenvironment through transcriptional changes in extracellular-matrix components, chemokines, and immunoregulatory factors. Therefore, Hippo signaling has both cell-autonomous and microenvironment-dependent functions.

5 Targeting Strategies for the Hippo Signaling Pathway

5.1 Targeting the TEAD Transcriptional Output

(1) Intervention in the Central Lipid Pocket

The TEAD central lipid pocket provides a structural site for direct intervention in the terminal transcriptional output of Hippo signaling. Early chemical tools such as Flufenamic Acid demonstrated that this pocket has small-molecule binding capacity. Subsequent strategies have further focused on designing reversible or covalent regulatory molecules around the central pocket and conserved cysteine residues to affect TEAD conformation, lipid modification, and YAP/TAZ-dependent transcription.

(2) Signaling Characteristics of TEAD Targeting

Direct TEAD inhibition occurs downstream of YAP/TAZ and therefore does not require increased YAP Ser127 phosphorylation or YAP exit from the nucleus. Reduced TEAD transcriptional output and persistent nuclear YAP localization can coexist mechanistically, which is also an important distinction between direct TEAD targeting and activation of upstream Hippo core kinases.

5.2 Targeting YAP/TAZ-TEAD Interactions

Verteporfin can reduce YAP/TEAD-related transcription in some models but also has protein-aggregation and other YAP-independent effects. Therefore, it is more suitable as a tool for functional intervention in YAP/TEAD rather than being defined as a highly selective direct YAP inhibitor. Strategies targeting the VGLL4-TEAD competitive interface can also restrict formation of the YAP-TEAD complex at the level of protein-protein interactions.

5.3 Targeting MST1/2 Core Kinases

XMU-MP-1 can inhibit MST1/2, weakening Hippo core kinase-mediated inhibition of YAP/TAZ and enhancing YAP-related regenerative programs in some tissue contexts. Therefore, MST1/2 inhibition is mainly applied in studies of core kinase function, injury repair, and tissue regeneration, and its classical direction of action is opposite to direct inhibition of YAP/TEAD. When the objective is to inhibit YAP/TAZ transcription in tumors, MST inhibitors should not be classified in the same pharmacological direction as TEAD inhibitors.

5.4 Targeting Upstream RTK-PI3K Inputs

Wortmannin and LY294002 can inhibit PI3K and reduce YAP nuclear accumulation or TEAD transcriptional output in some RTK-driven models. Because PI3K simultaneously regulates AKT, mTOR, cell survival, and metabolism, these compounds are mainly used to investigate RTK-PI3K-Hippo crosstalk rather than directly acting on core Hippo effector proteins.

5.5 Targeting Mechanotransduction

(1) F-actin Intervention

Cytochalasin D and Latrunculin A can interfere with Actin polymerization and F-actin structure, reduce stress fibers and cellular mechanical tension, and thereby inhibit mechanically dependent YAP/TAZ nuclear localization in some contexts. These tools are mainly used to validate the role of an intact Actin network in YAP/TAZ mechanotransduction.

(2) ROCK and Myosin II Intervention

Y-27632 reduces Rho-actomyosin signaling by inhibiting ROCK, Blebbistatin reduces cellular contractile tension by inhibiting Myosin II, and ML-7 acts on MLCK-related regulatory processes. These tools can affect actomyosin tension at the levels of the Rho downstream kinase, the myosin motor, and myosin light-chain regulation, respectively, and are used to analyze the relationship between mechanical force and YAP/TAZ nuclear translocation.

5.6 Targeting Energy-Stress Regulation

AICAR can enhance AMPK-related signaling and increase YAP inhibition under energy-stress conditions; Dorsomorphin (Compound C) is commonly used as a tool for AMPK-related mechanism research. AMPK can alter the classical Hippo kinase network and can also directly regulate YAP-TEAD interactions. Therefore, this strategy is mainly used to study the coupling between cellular energy status and Hippo transcriptional output.

5.7 Targeting YAP/TAZ Downstream Functions

Some models with high YAP/TAZ activity can involve effector nodes such as FOXM1 and COX-2 in cell-cycle or inflammation-related phenotypes. Thiostrepton can be used for FOXM1-related functional studies, and Celecoxib can be used for COX-2-related mechanistic analysis. Such interventions target specific downstream effects and cannot replace direct regulation of the YAP/TAZ-TEAD transcriptional network itself.

Table 2 Comparison of Major Targeting Levels of the Hippo Signaling Pathway

6 Products Related to Hippo Signaling Pathway Research

Table 3 Compounds Related to Hippo Core Signaling and YAP/TAZ Transcriptional Regulation

Table 4 Compounds Related to Hippo Mechanotransduction and Downstream Functions

The core of the Hippo signaling pathway is not information transmission between a single ligand and receptor but the integrated sensing of cell-contact status, the mechanical environment, and metabolic conditions. Multiple upstream inputs ultimately converge on the LATS-YAP/TAZ-TEAD axis and regulate cell growth, tissue homeostasis, and regeneration by controlling YAP/TAZ nuclear translocation and transcriptional function.

References

[1] Moya IM, et al. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol. 2019;20(4):211-226.

[2] Bae SJ, et al. Activation mechanisms of the Hippo kinase signaling cascade. Biosci Rep. 2018;38(4):BSR20171469. Published 2018 Aug 29.

[3] Del Re DP. The Hippo signaling pathway: implications for heart regeneration and disease. Clin Transl Med. 2014;3(1):27.

[4] Sebio A, et al. Molecular Pathways: Hippo Signaling, a Critical Tumor Suppressor. Clin Cancer Res. 2015;21(22):5002-5007.

[5] Fan R, et al. Regulation of Hippo pathway by mitogenic growth factors via phosphoinositide 3-kinase and phosphoinositide-dependent kinase-1. Proc Natl Acad Sci U S A. 2013;110(7):2569-2574.

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