Hippo–YAP/TAZ signaling pathway

The Hippo pathway is an evolutionarily conserved kinase cascade that restrains organ overgrowth by sequestering transcriptional co-activators YAP (Yes-associated protein; gene YAP1) and TAZ (transcriptional co-activator with PDZ-binding motif; gene WWTR1) in the cytoplasm. When the pathway is on (Hippo active), YAP/TAZ are phosphorylated, retained in the cytoplasm, and degraded. When the pathway is off (Hippo inactive), YAP/TAZ translocate to the nucleus, bind TEAD1–4 transcription factors, and drive a pro-growth, anti-apoptotic gene program.

In aging biology, the pathway has emerged as a critical transducer of mechanical signals — specifically the tissue stiffening that accumulates with age due to collagen crosslinking and fibrosis. Paradoxically, constitutive YAP/TAZ activation in aged, stiff tissues can both reinforce fibrosis and disturb stem cell fate, while the Hippo kinase arm may suppress regenerative responses needed to maintain tissue homeostasis. This makes the pathway a candidate aging driver in multiple tissues (liver, muscle, heart, lung) with emerging therapeutic targeting in cancer (mesothelioma) and — prospectively — in age-related fibrotic diseases.

Kinase cascade: pathway architecture

The core cascade operates as a sequential phosphorylation relay from plasma membrane to nucleus:

Upstream signals (cell density, polarity, ECM stiffness)
       ↓
  NF2 (Merlin) / RASSF proteins
       ↓
  MST1 (STK4) + MST2 (STK3)  ←── activated by dimerization + autophosphorylation (Thr183/Thr180)
       + SAV1 (Salvador) scaffold
       ↓
  LATS1 + LATS2  ←── activated by MST-mediated phosphorylation (Thr1079/Thr1041) + MOB1A/B co-activators
       ↓
  YAP1 (Ser127) + WWTR1/TAZ (Ser89) phosphorylated
       ↓
  14-3-3 binding → cytoplasmic retention
  β-TrCP E3 ubiquitin ligase recognition → proteasomal degradation

Key regulatory nodes:

Protein	Gene	Role	Note
MST1	STK4	Ste20-family kinase; core Hippo kinase	Autophosphorylates on T183; complexes with SAV1
MST2	STK3	Paralog of MST1; partially redundant	Double MST1/2 KO gives stronger phenotype than single
SAV1	SAV1	Scaffold for MST1/2 activation	WW-domain protein; named “Salvador” in Drosophila
LATS1	LATS1	NDR-family kinase; phosphorylates YAP/TAZ	Original mammalian homolog of Drosophila warts ¹
LATS2	LATS2	Paralog of LATS1	Shares substrates; tumor suppressor
MOB1A/B	MOB1A/B	LATS activating co-factor; recruited by MST phosphorylation	Required for full LATS kinase activation
YAP	YAP1	Transcriptional co-activator; Hippo effector	Phospho-Ser127 → 14-3-3; Ser381 → β-TrCP degradation
TAZ	WWTR1	Paralog of YAP; overlapping but distinct target genes	Phospho-Ser89 → 14-3-3; Ser311 → β-TrCP
TEAD1-4	TEAD1–4	Nuclear transcription factors; obligate YAP/TAZ partners	Bind YAP/TAZ via TEAD YAP-binding domain (YBD)
NF2	NF2	FERM-domain tumor suppressor; upstream Hippo activator	Loss in mesothelioma → YAP activation

Founding Drosophila genetics: The pathway was first defined in Drosophila through identification of warts (wts, LATS ortholog) as a tumor suppressor ¹ and subsequently hippo (hpo, MST ortholog) as the upstream kinase ². Mammalian studies confirmed conservation. YAP was established as the nuclear effector inactivated by LATS in 2007 ³.

ON state vs. OFF state

State	Hippo signal	LATS activity	YAP/TAZ	Transcriptional output
Hippo ON (pathway active)	High (cell density, soft matrix, polarity cues)	High	Phosphorylated → cytoplasmic retention + degradation	Growth-suppressive; quiescence; differentiation
Hippo OFF (pathway inactive)	Low (sparse cells, stiff matrix, injury)	Low	Unphosphorylated → nuclear import → TEAD binding	Pro-growth: CTGF, CYR61, ANKRD1, MYC, AXL, BIRC5

Key YAP/TAZ target genes when pathway is OFF (nuclear YAP/TAZ active):

CTGF (connective tissue growth factor) — fibrosis driver; ECM production
CYR61 (CCN1) — matrix protein; angiogenesis, wound healing
ANKRD1 — mechanosensitive transcriptional cofactor
MYC — cell cycle progression
AXL — receptor tyrosine kinase; survival, drug resistance
BIRC5 (survivin) — anti-apoptotic

Mechanosensing: YAP/TAZ as mechanical rheostat

The most physiologically important non-cell-autonomous input to YAP/TAZ is substrate stiffness and cell geometry, independent of the MST–LATS kinase cascade. Dupont et al. 2011 established that YAP/TAZ serve as primary transducers of extracellular matrix stiffness and cell morphology — stiff substrates and spread cell shapes activate nuclear YAP/TAZ even in the absence of canonical Hippo kinase signaling ⁴. This mechanosensing function involves:

Actomyosin tension — F-actin polymerization and Rho/ROCK-mediated cytoskeletal tension promote nuclear YAP/TAZ by preventing LATS-mediated phosphorylation; disruption of F-actin (cytochalasin D, latrunculin) drives YAP/TAZ to the cytoplasm.
Cell density — high confluence activates Hippo kinase arm (E-cadherin junctions, α-catenin, AMOT/Angiomotin family); low density / sparse cells allow YAP/TAZ nuclear entry.
Cell shape — spread, elongated cells on stiff surfaces activate YAP/TAZ; round cells on soft surfaces suppress it.
Fluid shear stress — laminar shear stress in endothelial cells suppresses YAP/TAZ; disturbed flow (atheroprone) activates it (relevant to atherosclerosis).

Dimension	Status
Pathway conserved in humans?	yes
Mechanosensing function conserved?	yes (human cells; primary human fibroblasts, MSCs, cardiomyocytes)
Replicated in humans (aging stiffness)?	in-progress

Aging biology

Tissue stiffness increases with age → constitutive YAP/TAZ activation

Extracellular matrix (ECM) accumulates collagen crosslinks (LOX-catalyzed) and fibronectin during aging, stiffening most tissues (muscle, liver, heart, lung, vasculature). Because YAP/TAZ activity is mechanosensitively coupled to substrate stiffness, aged tissues drive constitutive YAP/TAZ nuclear localization in resident cells, even in the absence of injury.

In aged skeletal muscle, ECM stiffness was shown to increase with age, and fibroblasts seeded onto age-mimetic stiff substrates showed elevated YAP/TAZ levels — the same fibrogenic conversion seen in naturally aged muscle tissue. Young fibroblasts on stiff (aged-equivalent) matrices upregulated fibrogenic gene programs, demonstrating that the mechanical signal alone is sufficient ⁵. needs-human-replication — this was a murine study; human aging muscle ECM stiffness → YAP/TAZ activation has not been systematically quantified in vivo.

Hepatic aging: YAP activation in aged hepatocytes

Yimlamai et al. 2014 used conditional Hippo pathway manipulation in mouse liver to show that Hippo pathway activity determines hepatocyte vs. biliary cell fate — YAP nuclear activation reprograms adult hepatocytes toward a biliary progenitor state ⁶. Although this study was primarily developmental, its implication for aging is that constitutive YAP activation in aged, stiff hepatocytes may contribute to aberrant cell identity and age-related liver dysfunction. needs-replication — the direct aged-hepatocyte phenotype in this context has not been independently reproduced.

Senescence reinforcement via tissue stiffening

A proposed feedback loop links cellular-senescence and the Hippo pathway in aging tissues:

Senescent cells secrete SASP (see sasp) — including TGF-β, IL-6, MMPs.
SASP promotes local ECM remodeling → stiffening.
Increased stiffness → YAP/TAZ nuclear activation in neighboring cells → CTGF, CYR61 → further ECM deposition.
Loop reinforces fibrosis and spreads the senescence-associated tissue phenotype.

This feedback is mechanistically plausible and supported by in vitro evidence but has not been demonstrated as a causal loop in aged tissues in vivo. no-mechanism needs-replication

AMPK–Hippo cross-talk

AMPK activation suppresses YAP/TAZ activity through multiple mechanisms: direct LATS activation, inhibition of Rho/ROCK (reducing actomyosin tension), and suppression of TGF-β-driven myofibroblast programs ⁷. This positions ampk activators (metformin, exercise) as indirect Hippo pathway modulators and suggests that metabolic decline with age (falling NAD+/AMPK activity) may permissively disinhibit YAP/TAZ in aged tissues. The functional significance of this cross-talk in human aging has not been established. needs-human-replication

Disease

Mesothelioma (NF2 loss)

Malignant pleural mesothelioma is the paradigm case of Hippo pathway loss-of-function cancer. ~40–50% of mesotheliomas harbor NF2 (Merlin) loss-of-function mutations; without NF2’s upstream Hippo activation, MST/LATS are insufficiently active and YAP/TAZ are constitutively nuclear. This makes YAP/TAZ hyperactivation a targetable vulnerability. needs-replication on the exact NF2 mutation prevalence figure.

Uveal melanoma

Activating mutations in GNAQ or GNA11 (Gα subunits) drive YAP/TAZ activation via Trio-RhoA-actomyosin signaling, bypassing the canonical kinase cascade. YAP is a transcriptional mediator of GNAQ oncogenic signaling in uveal melanoma.

Cardiac fibrosis

Post-MI cardiomyocyte loss activates cardiac fibroblasts; YAP/TAZ drive fibroblast activation and fibrotic remodeling. Cardiac-specific Hippo pathway loss (LATS1/2 KO in cardiomyocytes) promotes regeneration but also pathological hypertrophy — the regenerative vs. fibrotic balance depends on cell type and context. Connects to cardiac-fibrosis and heart-failure.

Therapeutic landscape

Verteporfin (YAP–TEAD disruptor)

Verteporfin (benzoporphyrin derivative; approved as photosensitizer for AMD photodynamic therapy) was identified as a small-molecule disruptor of the YAP–TEAD protein–protein interaction ⁸. In cell-based assays it suppresses YAP/TAZ target gene expression and inhibits YAP-driven tumorigenic growth. At doses used in photodynamic therapy, it is not a pure YAP/TAZ inhibitor (has additional reactive oxygen species effects). Preclinical data in multiple cancer models; limited early-stage clinical exploration for YAP-driven cancers. dose-response-unclear — the concentration range relevant to YAP/TAZ inhibition vs. PDT phototoxicity overlaps imperfectly, complicating interpretation.

VT3989 (TEAD palmitoylation-pocket inhibitor, Phase 1/2)

VT3989 is a first-in-class oral inhibitor that binds the lipid-binding pocket in the TEAD transcription factor (the palmitoylation site), preventing TEAD from serving as a coactivator of YAP/TAZ-dependent transcription. A Phase 1/2 trial in 172 patients (135 with mesothelioma) reported ⁹:

Overall response rate (ORR): 32% in mesothelioma (optimized dose cohort)
Disease control rate: 86%
Median progression-free survival: 10 months
Safety: predominantly grade 1–2 proteinuria and peripheral edema; proteinuria reversible with dose adjustment
Regulatory status: FDA orphan drug + fast-track designation for mesothelioma

This is the first clinical validation that pharmacological YAP/TAZ–TEAD disruption is tolerable and efficacious in humans. long-term-unknown — long-term safety in a non-oncology aging context is not established; the trial population is cancer patients.

K-975 / IAG933 (TEAD lipid-pocket inhibitors, preclinical)

K-975 (Kyowa Kirin) and IAG933 (Novartis) also target the TEAD palmitoylation pocket. K-975 showed anti-tumor activity in mesothelioma xenografts; IAG933 is in early-phase trials. Neither has published aging-specific data. needs-replication

Aging-specific therapeutic potential

No clinical intervention targeting the Hippo–YAP/TAZ pathway has been tested for aging indications. The mechanistic case rests on:

Tissue stiffness → constitutive YAP/TAZ → fibrosis → organ dysfunction loop.
YAP/TAZ suppression of regenerative proliferation in stem cell niches (e.g., muscle satellite cells, hepatic progenitors).

Open Targets lists YAP1 and WWTR1 as tier 1 druggable targets (clinical drug exists — VT3989/verteporfin) for several fibrotic and oncologic indications. unsourced for the specific druggability-tier number pull from Open Targets — verify against platform.opentargets.org/target/ENSG00000137693 (YAP1).

Cross-pathway connections

wnt-beta-catenin — YAP/TAZ interact with β-catenin and Axin; Hippo-independent YAP/TAZ activation can amplify Wnt target genes; the two pathways cooperate in intestinal homeostasis and cancer.
pi3k-akt-pathway — PI3K/AKT can suppress LATS1/2 activity (via NDR kinases), disinhibiting YAP/TAZ; PI3K inhibition partially restores Hippo activity in some cancer contexts.
ampk — AMPK suppresses YAP/TAZ (see above); a key mechanistic bridge between metabolic sensing and mechanical signaling.
tgf-beta — TGF-β cooperates with nuclear YAP/TAZ to drive fibrotic programs; they co-regulate CTGF, CYR61, and myofibroblast differentiation genes. See R20 TGF-β pathway page.
nf-kb — SASP cytokines (NF-κB targets) induce ECM stiffening (via TGF-β, IL-6) → YAP/TAZ activation — a pathway linking chronic-inflammation to mechanical YAP/TAZ signaling.

Limitations and gaps

Human aging data is sparse. Most aging-relevant evidence for Hippo–YAP/TAZ is from mouse models or engineered cell culture systems; no prospective human aging cohort data exists. needs-human-replication
Kinase-independent YAP/TAZ regulation. A large fraction of YAP/TAZ activity in normal adult tissue is regulated mechanically (F-actin/Rho), not through the MST–LATS cascade. Pharmacological Hippo kinase activation may be insufficient to suppress nuclear YAP/TAZ in stiff aged ECM. no-mechanism
TEAD inhibitor aging safety unknown. TEAD inhibitors (VT3989, K-975) have been tested only in cancer; long-term effects on tissue homeostasis, stem cell pools, and organ regeneration in a healthy aging context are unknown. long-term-unknown
Feedback loop directionality. The senescence-stiffness-YAP/TAZ loop is mechanistically plausible but not demonstrated causally in aged animals. needs-replication
Paralog redundancy. YAP and TAZ, and LATS1/LATS2, are partially redundant; tissue-specific compensation complicates genetic dissection. Most studies knock out only one paralog.
Upstream MST1/2 biology in aging. Whether MST1/2 kinase activity changes with age (and in which direction, in which tissues) is not systematically characterized. unsourced
Canonical ID gaps. WikiPathways ID for Hippo pathway was not confirmed during this extraction; left null in frontmatter. needs-canonical-id

Footnotes

doi:10.1101/gad.9.5.534 · in-vivo (Drosophila) · genetic screen · model: Drosophila melanogaster · Justice RW et al., Genes & Development 1995 · identified warts as Drosophila tumor suppressor encoding LATS kinase homolog; 950 citations ↩ ↩²
doi:10.1038/8484 · DOI not confirmed in a local paper archive (not found) — cited as Tao W et al., Nature Genetics 1999, “Mutations in lats/wts affect temporal aspects of tissue growth” · unsourced — verify DOI before relying on this citation; use Crossref to confirm ↩
doi:10.1101/gad.1602907 · in-vitro + in-vivo (mouse) · mechanistic study · model: HEK293, MCF10A, mouse liver · Zhao B et al., Genes & Development 2007 · established LATS-mediated YAP phosphorylation (Ser127) and cytoplasmic retention as core Hippo output; 3,075 citations ↩
doi:10.1038/nature10137 · in-vitro (human cells, multiple lines) · mechanistic study · model: MCF10A, human fibroblasts, MSCs · Dupont S et al. (Piccolo lab), Nature 2011 · YAP/TAZ as primary transducers of ECM stiffness and cell geometry; 5,544 citations; high confidence ↩
doi:10.1111/acel.12578 · in-vitro + ex-vivo · mechanistic study · model: murine and human skeletal muscle ECM; primary fibroblasts · Stearns-Reider KM et al., Aging Cell 2017 · aged muscle ECM stiffening drives fibrogenic conversion of stem cells via YAP/TAZ; reversible with substrate modulation; 227 citations ↩
doi:10.1016/j.cell.2014.03.060 · in-vivo (mouse) · genetic manipulation · model: mouse liver (Cre-lox conditional) · Yimlamai D et al., Cell 2014 · Hippo pathway activity controls hepatocyte vs. biliary cell fate; YAP nuclear activation reprograms hepatocytes; 865 citations ↩
doi:10.1007/s10522-023-10072-9 · review · model: literature synthesis · Salminen A, Biogerontology 2024 · AMPK signaling inhibits myofibroblast differentiation via suppression of TGF-β, NF-κB, STAT3, and YAP/TAZ pathways; 16 citations; low primary evidence weight — use as pointer to primary sources ↩
doi:10.1101/gad.192856.112 · in-vitro + in-vivo (mouse xenograft) · pharmacological study · model: HEK293, NF2-mutant cancer lines, mouse xenograft · Liu-Chittenden Y et al., Genes & Development 2012 · genetic and pharmacological (verteporfin) disruption of TEAD–YAP complex suppresses YAP oncogenic activity; 1,441 citations ↩
doi:10.1038/s41591-025-04029-3 · phase 1/2 clinical trial · n=172 (135 mesothelioma) · model: human (mesothelioma and other solid tumors) · Yap TA et al., Nature Medicine 2025 · VT3989 TEAD palmitoylation inhibitor; ORR 32%, DCR 86%, mPFS 10 months in mesothelioma; closed-access — not available in a local paper archive; numerics unverified against PDF no-fulltext-access ↩

🧬 Aging Wiki

Explorer

hippo-yap-taz