Abstract
The Hippo pathway controls tissue growth and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. Recent genetic studies in Drosophila identified Kibra as a novel regulator of Hippo signaling. Human KIBRA has been associated with memory performance and cell migration. However, it is unclear whether or how KIBRA is connected to the Hippo pathway in mammalian cells. Here, we show that KIBRA associates with and activates Lats (large tumor suppressor) 1 and 2 kinases by stimulating their phosphorylation on the hydrophobic motif. KIBRA overexpression stimulates the phosphorylation of Yes-associated protein (YAP), the Hippo pathway effector. Conversely, depletion of KIBRA by RNA interference reduces YAP phosphorylation. Furthermore, KIBRA stabilizes Lats2 by inhibiting its ubiquitination. We also found that KIBRA mRNA is induced by YAP overexpression in both murine and human cells, suggesting the evolutionary conservation of KIBRA as a transcriptional target of the Hippo signaling pathway. Thus, our study revealed a new connection between KIBRA and mammalian Hippo signaling.
Highlights
Components of the Hippo network are highly conserved in mammals [3, 15]
We show that KIBRA associates with both Lats1 and Lats2 to regulate the Hippo signaling activity in human cells
Kibra was recently identified as a regulator of the Hippo pathway by three independent groups [23,24,25]
Summary
Components of the Hippo network are highly conserved in mammals [3, 15]. Several human orthologs of the Hippo signaling components can rescue the respective Drosophila mutants in vivo [7, 12, 14]. We show that KIBRA associates with both Lats1 and Lats2 to regulate the Hippo signaling activity in human cells. KIBRA Associates with Lats1 and Lats2—To further characterize the function of KIBRA and to explore the relationship between KIBRA and the Hippo signaling in mammalian cells, we generated an anti-KIBRA antibody and performed immunoprecipitations on lysates of HEK293T cells.
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