Abstract IA34: Hippo signaling in development and cancer

Abstract

Abstract The Hippo signaling pathway regulates organ size and tissue homeostasis in diverse species from Drosophila to mammals. Central to the Hippo pathway is a functionally conserved kinase cascade leading from the Ste20-like protein kinase Hippo (Hpo) (Mst1/2 in mammals) and the NDR family kinase Warts (Lats1/2 in mammals) to the transcription factor complex formed by the coactivator Yorkie (Yki) (YAP/TAZ in mammals) and its major DNA-binding partner Scalloped (Sd) (TEAD1/2/3/4 in mammals). Inactivation of the Hippo pathway tumor suppressors or overexpression/activation of the YAP oncoprotein results in uncontrolled growth and tumorigenesis in transgenic mouse models and has been implicated in diverse human cancers. Compared to the core kinase cascade leading from Hpo to Yki, signaling events upstream of the Hippo kinase cascade are less well understood. My presentation will focus on Merlin/NF2, which encodes a member of the ezrin, radixin, moesin (ERM) family of membrane-cytoskeleton adapter proteins. Merlin/NF2 was discovered twenty years ago as a tumor suppressor underlying Neurofibromatosis type II, an autosomal dominant disorder characterized by the development of benign schwannomas, meningiomas and ependymomas. Although it is generally believed that Merlin/NF2 impacts cell signaling as a membrane-cytoskeleton scaffold, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo. These genetic findings have led to the prevailing view in the field that Merlin functions upstream of Hpo in a linear biochemical pathway, even though the genetic epistasis is equally compatible with Merlin and Hpo acting in parallel to promote Hippo signaling output. Using a combination of genetics, cell biology and biochemistry, we investigated the molecular relationship between Merlin/NF2 and the Hippo pathway in both Drosophila and mammals. In contrast to the commonly assumed linear pathway of Merlin/NF2 functioning through Hpo, we show that in both Drosophila and mammals, Merlin/NF2 promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo. Instead, Merlin/NF2 directly binds and recruits the effector kinase Wts to plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation and activation by the membrane-associated Hpo-Sav kinase complex. Accordingly, disease-causing mutations in Merlin/NF2 impair its ability to bind/recruit Wts to plasma membrane. Conversely, gain-of-function mutations in Merlin/NF2 potentiate its ability to bind/recruit Wts to plasma membrane. Our studies therefore uncover a critical function of Merlin in spatial organization of Hippo signaling at the plasma membrane. Citation Format: Duojia Pan. Hippo signaling in development and cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA34.