title: WIP Drives Tumor Progression through YAP/TAZ-Dependent Autonomous Cell Growth.
abstract: In cancer, the deregulation of growth signaling pathways drives changes in the cell's architecture and its environment that allow autonomous growth of tumors. These cells then acquire a tumor-initiating "stemness" phenotype responsible for disease advancement to more aggressive stages. Here, we show that high levels of the actin cytoskeleton-associated protein WIP (WASP-interacting protein) correlates with tumor growth, both of which are linked to the tumor-initiating cell phenotype. We find that WIP controls tumor growth by boosting signals that stabilize the YAP/TAZ complex via a mechanism mediated by the endocytic/endosomal system. When WIP levels are high, the β-catenin Adenomatous polyposis coli (APC)-axin-GSK3 destruction complex is sequestered to the multi-vesicular body compartment, where its capacity to degrade YAP/TAZ is inhibited. YAP/TAZ stability is dependent on Rac, p21-activated kinase (PAK) and mammalian diaphanous-related formin (mDia), and is Hippo independent. This close biochemical relationship indicates an oncogenic role for WIP in the physiology of cancer pathology by increasing YAP/TAZ stability.
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain; Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gargini
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Escoll
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: García
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), 28040 Madrid, Spain; Biomedical Research Institute I+12, University Hospital 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain. Electronic address: fwandosell@cbm.csic.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Wandosell
authors.affiliation: Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain. Electronic address: ianton@cnb.csic.es.
authors.forename: Inés María
authors.initials: IM
authors.lastname: Antón
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D018450:Disease Progression; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D057146:Multivesicular Bodies / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D058105:Polymerization; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C109903:WIPF1 protein, human; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex
keywords: Hippo pathway; WIPF1; YAP/TAZ; actin dynamics; breast cancer; glioma; multivesicular body; proliferation; tumor initiating cell; β-catenin destruction complex