The centrosomal protein Lats2 is a phosphorylation target of Aurora‐A kinase

Abstract

Human Lats2, a novel serine/threonine kinase, is a member of the Lats kinase family that includes the Drosophila tumour suppressor lats/warts. Lats1, a counterpart of Lats2, is phosphorylated in mitosis and localized to the mitotic apparatus. However, the regulation, function and intracellular distribution of Lats2 remain unclear. Here, we show that Lats2 is a novel phosphorylation target of Aurora-A kinase. We first showed that the phosphorylated residue of Lats2 is S83 in vitro. Antibody that recognizes this phosphorylated S83 indicated that the phosphorylation also occurs in vivo. We found that Lats2 transiently interacts with Aurora-A, and that Lats2 and Aurora-A co-localize at the centrosomes during the cell cycle. Furthermore, we showed that the inhibition of Aurora-A-induced phosphorylation of S83 on Lats2 partially perturbed its centrosomal localization. On the basis of these observations, we conclude that S83 of Lats2 is a phosphorylation target of Aurora-A and this phosphorylation plays a role of the centrosomal localization of Lats2.

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

“…Furthermore, elevated levels of Lat2, whose induction was at least partially affected by Fbw7 expression, inhibited drug-induced polyploidy. It is conceivable that the missing link connecting Fbw7 and the p53 pathway is Aurora A, which interacts and phosphorylates both Lats2 and p53 (Katayama et al, 2004;Liu et al, 2004;Toji et al, 2004). However, the existence of additional yet unknown Fbw7-controlled proteins that affect the p53 pathway is not excluded.…”

“…The vector for expression of shRNA against Fbw7 was kindly provided by Dr B Clurman. The expression vector for 6 Â Myc-Lats2 was previously described (Toji et al, 2004). The expression vector for the hyperstable form of cyclin E was kindly provided by Dr M Madryj, and has been described previously (Libertini et al, 2005).…”

“…These phosphorylations reduce p53 levels and transcriptional activity (Katayama et al, 2004;Liu et al, 2004). Aurora A also phosphorylates Lats2, a serine/threonine kinase considered to be a tumor suppressor which controls M phase transit and activation of the p53-dependent tetraploidy checkpoint (Toji et al, 2004;Aylon et al, 2006).…”

RASSF1A interacts with and activates the mitotic kinase Aurora-A

“…The construct of GST-Lats2-79-118 was a kind gift from Dr H Nojima (Osaka University, Japan) (Toji et al, 2004). GST-Lats2-79-118 protein was purified using glutathione sepharose 4B (Amersham, Piscataway, NJ, USA) according to the manufacturer's instructions.…”

A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization

“…The gene encoding Lats2, also known as Kpm (Hori et al 2000;Yabuta et al 2000), resides in a chromosomal region that exhibits frequent loss of heterozygosity (LOH) in human cancers (Yabuta et al 2000), consistent with the idea that it, too, is a tumor suppressor. Human Lats2 is a centrosomal protein (Toji et al 2004), and recent work suggests that it plays a role in regulating the formation of the mitotic spindle apparatus (Abe et al 2006). Clues from overexpression experiments suggest that excess Lats2 can cause G2/M arrest (Kamikubo et al 2003), G1/S arrest (Li et al 2003), or apoptosis (Ke et al 2004).…”