The Hippo signaling pathway controls organ size by regulating proliferation and apoptosis. In Drosophila, loss of function in the Hippo signaling pathway in eye imaginal discs results in larger eyes because of extra interommatidial cells; similarly, decreased Hippo signaling in posterior follicle cells (PFCs) of the oocyte causes extra layers of follicular epithelium. The FERM domain proteins Merlin (Mer) and Expanded (Ex) control activation of the kinase Hippo (Hpo), which phosphorylates and activates the kinase Warts (Wts). Phosphorylation of the transcriptional coactivator Yorkie (Yki) by Wts prevents nuclear translocation of Yki and transcription of proliferation and survival genes. Three groups have demonstrated a role for the WW domain protein Kibra in modulating the activation of the Hippo signaling pathway. Loss of function of Kibra resulted in extra layers of follicular epithelium in oocytes and increased eye size, the latter of which was attributed to increased proliferation and decreased apoptosis of interommatidial cells. In contrast, overexpression of Kibra caused decreased eye size due to ectopic apoptosis. Genetic epistasis analysis indicated that Kibra acted at the same level as Mer and Ex, upstream of Hpo, and promoted Yki inactivation. Accordingly, RNA interference (RNAi) directed against Kibra resulted in decreased Hpo kinase activity and phosphorylation of Ser168 in Yki. Furthermore, transfection of Kibra stimulated phosphorylation of Thr1077 in Wts, an effect that was increased by coexpression with Mer or Ex. Coimmunoprecipitation experiments revealed that Kibra interacted with Mer and with Ex, but whether Kibra and Hpo and Kibra and Wts also interact is not as clear, with only some groups detecting these interactions. Immunofluorescence analysis indicated that Kibra, Mer, and Ex colocalized at apical membranes in imaginal disc cells. Human KIBRA associated with FRMD6 (the human ortholog of Ex) and NF2 (the human ortholog of Mer), and transfection of KIBRA stimulated phosphorylation of LATS1 and LATS2 (the human orthologs of Wts). Thus, Kibra is an evolutionarily conserved component of the Hippo signaling pathway.
J. Yu, Y. Zheng, J. Dong, S. Klusza, W.-M. Deng, D. Pan, Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev. Cell 18, 288–299 (2010). [PubMed]
A. Genevet, M. C. Wehr, R. Brain, B. J. Thompson, N. Tapon, Kibra is a regulator of the Salvador/Warts/Hippo signaling network. Dev. Cell 18, 300–308 (2010). [PubMed]
R. Baumgartner, I. Poernbacher, N. Buser, E. Hafen, H. Stocker, The WW domain protein Kibra acts upstream of Hippo in Drosophila. Dev. Cell 18, 309–316 (2010). [PubMed]