REGULATION AND FUNCTION OF KIBRA IN THE HIPPO SIGNALING PATHWAY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. KIBRA is a new component of the Hippo signaling pathway in Drosophila. Mechanisms by which KIBRA affects Hippo signaling and the function of KIBRA in mammalian cells are not clear. We demonstrated that KIBRA associates with and activates Lats1and Lats2. In addition, we showed that transfection of RNAi specific for KIBRA decreases and over-expression of KIBRA increases the cellular level of phosphorylated YAP, which is the downstream substrate/target of the Lats1/2 kinases. Interestingly, we found that KIBRA stabilizes Lats2 by inhibiting the ubiquitylation of Lats2. KIBRA prolongs the half-life of Lats2. KIBRA itself is a transcriptional target of the Hippo signaling pathway both in mouse and human cells. KIBRA promotes phosphorylation of S83 on Lats2, which is dependent on Aur-A kinase. Over-expression of KIBRA strongly stimulates Aur-A kinase activity revealed by Aur-A auto-phosphorylation level (p-T288). Furthermore, we were able to detect the interaction between Aur-A and KIBRA when these two proteins were co-transfected in 293T cells. We found that KIBRA is a phospho-protein, the phospho-level of KIBRA peaks at the G2/M phase. RNAi-knockdown of KIBRA disrupts the microtubule structure and affects the Aurora-A and Lats2 localization. KIBRA also controls centrosome maturation and chromosome alignment.