Hippo signaling

Hippo signaling
Name	Hippo signaling pathway
Organism	Metazoa
Discovery	1995
Key components	Salvador, Warts, Yorkie, MST1, LATS1, MOB1
Functions	organ size control, tissue regeneration, tumor suppression

Hippo signaling is a conserved kinase cascade that controls organ size, cell proliferation, apoptosis, and stem cell behavior in metazoans. Discovered through genetic screens in Drosophila and subsequently connected to mammalian orthologs studied in institutions like the Wellcome Trust Sanger Institute and Harvard Medical School, the pathway integrates diverse upstream cues to regulate transcriptional programs mediated by cofactors and transcription factors. Work on Hippo signaling has influenced research at centers such as the Broad Institute, Max Planck Society, and Cold Spring Harbor Laboratory and informed therapeutic strategies in cancer centers including Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center.

Overview

The core concept emerged from genetic analyses in Drosophila melanogaster labs led by investigators affiliated with University of Cambridge and University of Cambridge Department of Genetics, linking tumor suppressor loci to overgrowth phenotypes. Subsequent biochemical and structural studies at places like Massachusetts Institute of Technology and Stanford University School of Medicine identified conserved mammalian kinases and adapters. Seminal reviews in journals associated with Nature Publishing Group and Cell Press synthesized findings that bridged developmental biology at European Molecular Biology Laboratory with translational oncology at Johns Hopkins University School of Medicine. The pathway exemplifies conserved signaling paradigms also studied alongside Wnt signaling, Notch signaling, and TGF-beta signaling in comparative developmental programs at institutions such as University of California, San Francisco.

Molecular Components and Pathway

Core components include evolutionarily conserved kinases and scaffolds first mapped in screens performed by groups at University of Cambridge and Imperial College London. In mammals, the MST kinases discovered by teams at University of London phosphorylate LATS kinases characterized in studies from Yale School of Medicine and University of Pennsylvania Perelman School of Medicine, with MOB1 and SAV1 acting as adaptors elucidated by researchers at University of Oxford. Downstream effectors such as YAP and TAZ were cloned and functionally characterized in laboratories at University of California, San Diego and Columbia University Irving Medical Center, and their interactions with TEAD transcription factors were resolved by structural biology groups at Karolinska Institutet and European Synchrotron Radiation Facility. Upstream regulatory complexes include proteins identified in screens from Cold Spring Harbor Laboratory and Duke University School of Medicine, while membrane-associated sensors were characterized in studies from University of Tokyo and Peking University Health Science Center. Signal transduction mechanisms were clarified through biochemical work at Princeton University and genetic models developed at University of Edinburgh.

Regulation and Crosstalk

Regulatory inputs were dissected by consortia including teams at Wellcome Sanger Institute and Harvard Medical School, showing modulation by mechanical cues studied in biomechanics labs at California Institute of Technology and ETH Zurich. Crosstalk with pathways like Wnt signaling, PI3K–AKT signaling, and MAPK/ERK pathway was mapped in collaborative projects involving University College London and Johns Hopkins University, while interactions with polarity complexes characterized at University of Cambridge Department of Genetics and Max Planck Institute of Molecular Cell Biology and Genetics link to cytoskeletal regulators studied at University of Michigan. Post-translational modulation by ubiquitin ligases and phosphatases was revealed by biochemical groups at Scripps Research and Roche Pharmaceuticals Research Center, and metabolic regulation was explored by investigators at University of Oxford and ETH Zurich.

Physiological Roles and Developmental Functions

Functional roles were demonstrated across model organisms curated by museums and institutes such as Smithsonian Institution and Natural History Museum, London, with developmental contributions traced in lineage-tracing studies from labs at University of California, Berkeley and Max Planck Society. In organogenesis, work at Harvard Stem Cell Institute and University of Cambridge linked pathway activity to liver regeneration characterized at Salk Institute for Biological Studies and to cardiac growth programs studied at Mount Sinai Health System. Roles in stem cell niches were defined by stem cell centers including Karolinska Institutet and Weill Cornell Medicine, and neural development insights emerged from research at MIT McGovern Institute and University College London Institute of Neurology.

Implications in Disease and Therapeutics

Oncogenic dysregulation was reported in tumor genomics studies from The Cancer Genome Atlas consortium and clinical research at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute, implicating pathway components in hepatocellular carcinoma studies at National Cancer Institute and in breast cancer cohorts analyzed by teams at Dana-Farber and MD Anderson Cancer Center. Therapeutic targeting efforts have been pursued by biotech companies and translational centers including Genentech, Novartis Institutes for BioMedical Research, and GlaxoSmithKline focusing on YAP/TEAD inhibitors and upstream modulators. Fibrosis and regenerative medicine applications were explored in collaborations involving Cleveland Clinic and Stanford University School of Medicine, while rare genetic syndromes with pathway mutations were cataloged by clinical genetics groups at Great Ormond Street Hospital and Mayo Clinic.

Experimental Methods and Models

Key methods were developed across core facilities at Broad Institute and European Molecular Biology Laboratory, including genetic screens in Drosophila and CRISPR-based perturbations performed at Broad Institute and Wellcome Trust Sanger Institute. Biochemical assays and kinase activity measurements were standardized in labs at EMBL-EBI and Max Planck Institute for Biochemistry, while live imaging approaches were advanced at Janelia Research Campus and Allen Institute for Brain Science. Structural studies using crystallography and cryo-EM were published by teams at European Synchrotron Radiation Facility and Diamond Light Source, and organoid and xenograft models were implemented at Hubrecht Institute and Fred Hutchinson Cancer Research Center to probe therapeutic responses.

Category:Signal transduction pathways