Hippo is the master organ-size control pathway — discovered in Drosophila (Warts/Hippo phenotypes — oversized tissues) and conserved in mammals. The core is a kinase cascade that restrains the YAP and TAZ transcriptional coactivators. Inputs: contact inhibition (cell-cell + cell-matrix tension via Crumbs, NF2/Merlin, AMOT, α-catenin), mechanical cues (substrate stiffness via integrins, F-actin/RhoA), GPCR signaling (LPA, S1P, thrombin activate YAP via Rho-GTPases; many Gs-coupled inhibit it), and metabolic state. ON state (cascade active — Hippo "on"): MST1/2 (STK4/3) → LATS1/2 phosphorylation → LATS1/2 phosphorylates YAP-Ser127 + TAZ-Ser89 → 14-3-3 binding → cytoplasmic retention + β-TrCP-mediated degradation → YAP/TAZ inactive → tissue growth restrained. OFF state (cascade off — Hippo "off"): YAP/TAZ unphosphorylated → translocate to nucleus → bind TEAD1–4 transcription factors → drive proliferation + survival + stemness target genes (CTGF, CYR61, ANKRD1, BIRC5, MYC). Tumor-suppressor vs oncogene paradox: in healthy tissue, Hippo restrains growth. In cancer, YAP/TAZ are hyperactive (mesothelioma — NF2 loss; some hepatocellular carcinoma, breast cancer with chromosomal amplification at 11q22 — YAP locus). NF2 (merlin) is the classical tumor suppressor (neurofibromatosis type 2). Therapeutic landscape: verteporfin (originally a photodynamic agent for AMD) is the best-known YAP-TEAD interaction inhibitor; new YAP/TAZ-TEAD palmitoyl-pocket inhibitors entering trials (IK-930 / IAG933 / VT3989) — early efficacy in NF2-mutant mesothelioma. Statins have YAP-modulating activity (HMG-CoA reductase → reduced geranylgeranylation of RhoA → YAP inactivation), partly explaining cancer chemoprevention signals. Cross-links: cell cycle cdk (downstream growth control), wnt beta catenin (parallel developmental morphogen), pi3k akt signaling (RhoA crosstalk).
Organ Systems
musculoskeletal
cardiovascular
digestive
integumentary
Pathway Steps
contact / mechanical / GPCR inputs → NF2 / AMOT / Crumbs signal integration — via tissue tension + cell-cell contact + LPA/S1P GPCRs converge at the kinase cascade input. The Hippo pathway is unusual in lacking a single dedicated ligand/receptor — it integrates diffuse cues. Cell-cell contact (via NF2/Merlin, the angiomotins, Crumbs/Scribble polarity complexes) and mechanical signals (stiff ECM, tension, F-actin state) converge on the core kinases, while LPA/S1P GPCRs can switch it off — making YAP/TAZ central sensors of tissue architecture and mechanotransduction.
MST1/2 (STK4/3) active → LATS1/2 + MOB1 activation (phosphorylation) — via SAV1 scaffold; MST1/2 are core upstream kinases. The core kinase cassette: MST1/2 (the STK4/3 mammalian Hippo orthologs), scaffolded by SAV1, phosphorylate and activate LATS1/2 together with the MOB1 adaptor. This relay amplifies upstream growth-suppressive signals — loss of NF2 or the core kinases (as in mesothelioma and NF2-mutant tumors) leaves the brake off.
LATS1/2 active → YAP-Ser127 + TAZ-Ser89 phosphorylation — via 14-3-3 binding → cytoplasmic retention; β-TrCP → degradation. Active LATS1/2 phosphorylate YAP (Ser127) and the paralog TAZ (Ser89). Phospho-YAP/TAZ are caught by 14-3-3 proteins for cytoplasmic retention, and further phosphorylation flags them for β-TrCP–mediated proteasomal degradation — a two-step shutoff (sequester, then destroy) that keeps the coactivators out of the nucleus.
YAP / TAZ cytoplasmic + degraded → tissue growth restrained (Hippo ON) — via transcriptional coactivators absent from nucleus. When the cascade is ON (high cell density, confluent epithelium), YAP/TAZ stay cytoplasmic and degraded, so their target genes are silent and proliferation is restrained — the molecular basis of contact inhibition and organ-size control. Genetic inactivation of Hippo causes massive tissue overgrowth, first shown in Drosophila.
Hippo cascade OFF (low cell density, soft substrate) → YAP / TAZ nuclear translocation — via unphosphorylated YAP/TAZ enter nucleus to drive transcription. At low cell density or on a soft/remodeling matrix the kinases are inactive, so unphosphorylated YAP/TAZ accumulate and enter the nucleus. Because the OFF (growth-driving) state powers regeneration after injury, its persistent activation — e.g. via mechanical stiffening — is a driver of fibrosis.
YAP / TAZ + TEAD1–4 → CTGF + CYR61 + ANKRD1 + MYC transcription — via proliferation + survival + stemness program; tumor-promoting in cancer context. In the nucleus YAP/TAZ have no DNA-binding domain — they partner with TEAD1-4 transcription factors to switch on proliferation/survival/stemness genes (CTGF, CYR61, ANKRD1, MYC). YAP/TAZ-TEAD activity is oncogenic across many cancers, making the interaction a drug target — verteporfin disrupts YAP-TEAD, and TEAD palmitoylation-pocket inhibitors are in trials.
Known Modulators
rapamycin (inhibitor) — mTORC1 → YAP cross-talk (TSC2 axis); part of growth-restraint