KIBRA regulates Hippo signaling activity via interactions with large tumor suppressor kinases.
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.
Pubmed ID: 21233212
The Journal of biological chemistry
March 11, 2011
- Agency: NCRR NIH HHS, Id: 5P20-RR018759-07
- Adaptor Proteins, Signal Transducing
- Amino Acid Motifs
- Carrier Proteins
- Cell Line, Tumor
- Drosophila melanogaster
- HEK293 Cells
- Intracellular Signaling Peptides and Proteins
- Protein-Serine-Threonine Kinases
- Signal Transduction
- Tumor Suppressor Proteins