Category: signaling
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).