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

Ricardo Gargini,Maribel Escoll,Esther García,Ramón García-Escudero,Francisco Wandosell,Inés María Antón

doi:10.1016/j.celrep.2016.10.064

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.

Highlights

A common feature of many tumors is their dependence on survival signals such as upregulation of the phosphatidylinositol 3-kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) pathways (Hanahan and Weinberg, 2011), which allow some autocrine signaling
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

Summary

Introduction

A common feature of many tumors is their dependence on survival signals such as upregulation of the phosphatidylinositol 3-kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) pathways (Hanahan and Weinberg, 2011), which allow some autocrine signaling. Many tumor cell types depend on endo- or exocytosis for their growth, migration, and invasion (Joffre et al, 2011). The regulation of actin polymerization is central to coordinating receptor-mediated endocytosis as well as receptor recycling and degradation (Schafer, 2002). Some of these processes require actin cytoskeleton dynamics to coordinate cell proliferation and invasion, which are associated with metastasis. Several regulatory and actin-associated molecules, such as WASP (Wiskott-Aldrich syndrome protein) family proteins or WIP (WASP-interacting protein) participate in migration and invadopodium formation, which might sustain metastasis (Stevenson et al, 2012), but only a few have essential roles in cancer pathology

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Discussion

Conclusion