Abstract
Studies of brain-specific kinase 2 (BRSK2), an AMP-activated protein kinase (AMPK)-related kinase, and its homologs suggest that they are multifunctional regulators of cell-cycle progression. BRSK2, which contains a ubiquitin-associated (UBA) domain, is polyubiquitinated in cells. However, the regulatory mechanisms and exact biological function of BRSK2 remain unclear. Herein, we show that BRSK2 co-localizes with the centrosomes during mitosis. We also demonstrate that BRSK2 protein levels fluctuate during the cell cycle, peaking during mitosis and declining in G1 phase. Furthermore, Cdh1, rather than Cdc20, promotes the degradation of BRSK2 in vivo. Consistent with this finding, knock-down of endogenous Cdh1 blocks BRSK2 degradation during the G1 phase. The conserved KEN box of BRSK2 is required for anaphase-promoting complex/cyclosome-Cdh1 (APC/CCdh1)-dependent degradation. Additionally, overexpression of either BRSK2(WT) or BRSK2(ΔKEN) increases the percentage of cells in G2/M. Thus, our results provide the first evidence that BRSK2 regulates cell-cycle progression controlled by APC/CCdh1 through the ubiquitin-proteasome pathway.
Highlights
Brain-specific kinase 2 (BRSK2) was initially identified through sequence homology with the protein kinase domain of AMPK and is classified as an AMPK-related kinase [1]
BRSK2 Localizes to Centrosomes during Mitosis Recent evidence showed that the BRSK2 homologue BRSK1 (SADB), whose activity fluctuates during the cell cycle, localizes to centrosomes and controls centrosome duplication [17]
Similar to the BRSK1 localization, the images of subcellular localization showed that areas corresponding to the patterns of centrosomes were stained with BRSK2 in the mitosis phase
Summary
Brain-specific kinase 2 (BRSK2) was initially identified through sequence homology with the protein kinase domain of AMPK and is classified as an AMPK-related kinase [1]. A role for BRSK2 and its homologs in other molecular regulatory functions, especially cell cycle regulation, was reported recently. The yeast homolog of BRSK2 (human sequence similar to yeast-12, HUSSY-12) [15], phosphorylates c-tubulin in vitro [16]; another investigation reported that BRSK1 (SADB) phosphorylates c-tubulin on Ser 131 to control centrosome homeostasis [17]. These studies imply that BRSK2 plays an important role in the regulation of cell cycle progression
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