Kibra Functions as a Tumor Suppressor Protein that Regulates Hippo Signaling in Conjunction with Merlin and Expanded

Abstract

Summary The Hippo signaling pathway regulates organ size and tissue homeostasis from Drosophila to mammals. Central to this pathway is a kinase cascade wherein Hippo (Hpo), in complex with Salvador (Sav), phosphorylates and activates Warts (Wts), which in turn phosphorylates and inactivates the Yorkie (Yki) oncoprotein, known as the YAP coactivator in mammalian cells. The FERM domain proteins Merlin (Mer) and Expanded (Ex) are upstream components that regulate Hpo activity through unknown mechanisms. Here we identify Kibra (Kbr) as another upstream component of the Hippo signaling pathway. We show that Kbr functions together with Mer and Ex in a protein complex localized to the apical domain of epithelial cells, and that this protein complex regulates the Hippo kinase cascade via direct binding to Hpo and Sav. These results shed light on the mechanism of Ex and Mer function, and implicate Kbr as a potential tumor suppressor with relevance to neurofibromatosis.

WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma

“…have verified WWC2 directly binds to LATS1/2 via their WW domains, and phosphorylates and activates LATS1/2 22. Activated LATS1/2 phosphorylate YAP, which inhibited cell proliferation in mammalian cells 38, 39, 40. In confirmation that WWC2 activates the Hippo pathway in HCC, overexpression of WWC2 in SMMC‐7721 cells (which express low levels of WWC2) increased phosphorylation of both LATS and YAP, which has been previously shown to negatively regulate the Hippo pathway 11, 41, 42.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Two apical cytoskeleton-binding proteins, Merlin (Mer) and Expanded (Ex) , and Kibra, which interacts with Mer and Ex (Baumgartner et al, 2010;Genevet et al, 2010;Yu et al, 2010), were found to activate the Hippo pathway. Double mutations of these genes produce phenotypes closely resembling those caused by mutations of Hippo pathway components.…”

When pathways collide: collaboration and connivance among signalling proteins in development

“…Expanded can bind Hpo, and Merlin can bind Sav 71 . Interactions between Expanded and Merlin are promoted by Kibra, a cytoplasmic protein with two WW domains and a C2 domain that is essential for maximal Hippo pathway activation [71][72][73] . In addition, Kibra can bind Hpo, promoting its association with membranes, which may contribute to activation of the pathway.…”