Abstract
The Hippo pathway controls organ size and tumorigenesis by inhibiting cell proliferation and promoting apoptosis. KIBRA was recently identified as a novel regulator of the Hippo pathway. Several of the components of the Hippo pathway are important regulators of mitosis-related cell cycle events. We recently reported that KIBRA is phosphorylated by the mitotic kinases Aurora-A and -B. However, the role KIBRA plays in mitosis has not been established. Here, we show that KIBRA activates the Aurora kinases and is required for full activation of Aurora kinases during mitosis. KIBRA also promotes the phosphorylation of large tumor suppressor 2 (Lats2) on Ser(83) by activating Aurora-A, which controls Lats2 centrosome localization. However, Aurora-A is not required for KIBRA to associate with Lats2. We also found that Lats2 inhibits the Aurora-mediated phosphorylation of KIBRA on Ser(539), probably via regulating protein phosphatase 1. Consistent with playing a role in mitosis, siRNA-mediated knockdown of KIBRA causes mitotic abnormalities, including defects of spindle and centrosome formation and chromosome misalignment. We propose that the KIBRA-Aurora-Lats2 protein complexes form a novel axis that regulates precise mitosis.
Highlights
The memory-associated protein KIBRA regulates cell polarity and migration in non-neuronal cells and a cellular function of KIBRA in mitosis is not defined
large tumor suppressor 2 (Lats2) Inhibits Phosphorylation of KIBRA on Ser539—We previously reported that during mitosis Ser539 of KIBRA is phosphorylated by Aurora kinases and that KIBRA migrates differently on SDS-polyacrylamide gels depending on its phosphorylation status [40]
Identification of modulators and/or substrates of Aurora kinases is important for understanding the function and mechanisms of action of Aurora kinase family proteins and the basic principles of cell cycle regulation
Summary
The memory-associated protein KIBRA regulates cell polarity and migration in non-neuronal cells and a cellular function of KIBRA in mitosis is not defined. Consistent with playing a role in mitosis, siRNA-mediated knockdown of KIBRA causes mitotic abnormalities, including defects of spindle and centrosome formation and chromosome misalignment. At the centrosome Lats is phosphorylated on Ser by Aurora-A (a mitotic kinase that plays critical roles in spindle assembly, centrosome function, and mitotic progression [2, 12]) and the phosphorylation of Lats on Ser is required for its centrosome localization during mitosis [13]. Lats and its homolog Lats are core kinases of the Hippo signaling pathway, which plays critical roles in controlling organ size, tumorigenesis, stem cell self-renewal, and cell contact inhibition by regulating both cell proliferation and apoptosis (14 –16). Recent studies demonstrated that some other members of the Hippo pathway such as Mst, Mst, Mob1/Mats, and WW45 are involved in mitotic regulation [17,18,19,20,21,22]
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