WIP Drives Tumor Progression through YAP/TAZ-Dependent Autonomous Cell Growth

• Published in: Cell reports (Cambridge) Vol. 17; no. 8; pp. 1962 - 1977
• Main Authors: Gargini, Ricardo, Escoll, Maribel, García, Esther, García-Escudero, Ramón, Wandosell, Francisco, Antón, Inés María
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.11.2016
• Subjects: actin dynamics; Actins - metabolism; Adaptor Proteins, Signal Transducing - metabolism; beta Catenin - metabolism; breast cancer; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytoskeletal Proteins - metabolism; Disease Progression; Endocytosis; Endosomes - metabolism; Epithelial-Mesenchymal Transition; glioma; Hippo pathway; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Multivesicular Bodies - metabolism; multivesicular body; Neoplasm Invasiveness; Neoplasms - metabolism; Neoplasms - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phenotype; Phosphoproteins - metabolism; Polymerization; proliferation; Proteasome Endopeptidase Complex - metabolism; Protein Stability; Proteolysis; Signal Transduction; Trans-Activators; Transcription Factors; tumor initiating cell; WIPF1; YAP/TAZ; β-catenin destruction complex; Hippo pathway; proliferation; WIPF1; YAP/TAZ; tumor initiating cell; multivesicular body; β-catenin destruction complex; glioma; breast cancer; actin dynamics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.10.064

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. [Display omitted] •High WIP levels promote YAP/TAZ stability and correlate with poor patient survival•WIP regulates the endocytic/endosomal system via Rac/PAK and the formin mDia•WIP expression leads to sequestration of the β-catenin destruction complex in MVB•WIP reduction impairs in vivo glioblastoma growth, notably increasing mouse survival Gargini et al. show that WIP stabilizes the transcriptional co-activators YAP/TAZ via the endocytic/endosomal system, suggesting that WIP has oncogenic functions. WIP promotes and coordinates cell proliferation, stemness, and invasiveness to drive tumor progression.