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

• DOI: 10.1016/j.celrep.2016.10.064
• Publication Date: 2016-11-16T00:20:36Z
• Authors: Ricardo Gargini; Maribel Escoll; Esther García; Ramón García-Escu...; Francisco Wandosell; Inés María Antón
• Keywords: Hippo signaling pathway; Formins; Tumor progression

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.