Calmodulin activation of Aurora-A kinase (AURKA) is required during ciliary disassembly and in mitosis

Abstract

This study demonstrates for the first time that binding of calcium-activated calmodulin to a minimal interaction site within the disordered N-terminal domain is required for the essential Aurora-A activity in mitosis and in regulation of ciliary disassembly.

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

“…Nedd9 binding and activation of Aurora-A is required for ciliary resorption (12,31), and we have observed that Aurora-A expression is elevated in the cystic tissue of patients with ADPKD (20). These results suggested the hypothesis that defects in Aurora-A activation at cilia might underlie the observed trafficking and morphological defects.…”

INPP5E interacts with AURKA, linking phosphoinositide signalling to primary cilium stability

“…Increases in cellular levels of phospho-AURKA are associated with an increase in cilia disassembly (Pugacheva et al, 2007;Plotnikova et al, 2012) and similar defects are observed in Inpp5e 2/2 cells (Bielas et al, 2009). To determine whether there was a shared functional basis to these phenotypes, we serum starved fibroblasts from wild-type and Inpp5e 2/2 mice and profiled cilia disassembly upon the addition of serum in the presence or absence of an AURKA inhibitor (C1368) or vehicle control (DMSO).…”

“…Plasmids, cell culture and inhibitors AURKA and catalytically inactive AURKA (K162R) were expressed from pcDNA3.1-mRFP vector (Plotnikova et al, 2012), murine wild-type INPP5E, INPP5E D480N and INPP4B were expressed from pcDNA3.1-HA, and FLAG-INPP5E was expressed from pcDNA3.1-Flag. V5-tagged human wild-type INPP5E and INPP5E containing Joubert syndrome (JBTS) missense mutations were cloned into pLenti6.2/V5-DEST (Life Technologies).…”

“…AURKA localises to the ciliary basal body in mammalian cells, where it regulates ciliary disassembly through interactions with NEDD9 and other proteins (Pugacheva et al, 2007). Increases in phosphorylation of AURKA are linked to increased cilia disassembly (Pugacheva et al, 2007;Plotnikova et al, 2012), whereas Inpp5e 2/2 MEFs have ciliary disassembly defects (Jacoby et al, 2009). In serum-starved primary fibroblasts from Inpp5e 2/2 mice, we observed an increase in the level of phosphorylated AURKA compared with that of wild-type cells.…”

“…In addition to other ciliopathy features, Inpp5e 2/2 mice also develop renal cysts, a phenotype that is frequently associated with primary cilium defects (Jacoby et al, 2009). Taking into account the previously described role for AURKA in PKD (Plotnikova et al, 2011) and in the regulation of primary cilia stability (Pugacheva et al, 2007;Plotnikova et al, 2012), we evaluated the impact of altered AURKA function in a cellular model of INPP5E-dependent cyst formation. To examine whether the AURKA-INPP5E complex impacted upon these features, we depleted INPP5E from IMCD3 cells and grew them in a threedimensional (3D) Matrigel matrix.…”