Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.
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 as another upstream component of the Hippo signaling pathway. We show that Kibra 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 Kibra as a potential tumor suppressor with relevance to neurofibromatosis.
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
Jianzhong
J
Yu
Yonggang
Y
Zheng
Jixin
J
Dong
Stephen
S
Klusza
Wu-Min
WM
Deng
Duojia
D
Pan
D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D016764:Cell Polarity; D004330:Drosophila / Q000235:genetics / Q000254:growth & development* / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D017344:Genes, Insect; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D046912:Multiprotein Complexes; D025581:Neurofibromin 2 / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C497759:N protein, Drosophila; C513637:WWC1 protein, human; C503814:Yki protein, Drosophila; C085090:ex protein, Drosophila; C548168:kibra protein, Drosophila; C099885:merlin, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases