HEF1-Dependent Aurora A Activation Induces Disassembly of the Primary Cilium

Abstract

The mammalian cilium protrudes from the apical/lumenal surface of polarized cells and acts as a sensor of environmental cues. Numerous developmental disorders and pathological conditions have been shown to arise from defects in cilia-associated signaling proteins. Despite mounting evidence that cilia are essential sites for coordination of cell signaling, little is known about the cellular mechanisms controlling their formation and disassembly. Here, we show that interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly. We show that this pathway is both necessary and sufficient for ciliary resorption and that it constitutes an unexpected nonmitotic activity of AurA in vertebrates. Moreover, we demonstrate that small molecule inhibitors of AurA and HDAC6 selectively stabilize cilia from regulated resorption cues, suggesting a novel mode of action for these clinical agents.

CPAP promotes timely cilium disassembly to maintain neural progenitor pool

“…To gain insight into how CPAP coordinates cilium disassembly, we tested whether CPAP could interact with proteins, which are known to play roles in cilium disassembly such as Nde‐1, Aurora A, HDAC6 and OFD1 (Pugacheva et al , 2007; Kim et al , 2011; Tang et al , 2013; hereafter referred to as Cilium Disassembly Complex, CDC). Indeed, cytoplasmic CPAP co‐immunopurified with components of the CDC (CPAP‐CDC; Fig 3A).…”

RASSF1A interacts with and activates the mitotic kinase Aurora-A

“…For instance, activation of Aurora-A by TPX2 is required for bipolar-spindle assembly (Trieselmann et al, 2003;Tsai et al, 2003), whereas activation of Aurora-A by Ajuba is essential for mitotic entry . Activation of Aurora-A by HEF-1 in a nonmitotic pathway is mandatory for the disassembly of the primary cilium (Pugacheva et al, 2007). RASSF1A is a residential centrosomal protein, whereas Aurora-A is recruited to centrosomes during G 2 /M phase.…”

Cellular defence or viral assist: the dilemma of HDAC6

“…Alternative splicing [161] 14-3-3z Lys 49 /Lys 120 Suppression of growth and survival signalling [162] (GRK2) [35,36], aurora A [37] and protein kinase C isoform z (PKCz) [38], are also found to phosphorylate and increase HDAC6 tubulin deacetylase activity at positions that remain undefined. Another example of enhanced HDAC6 activity by phosphorylation is provided by protein kinase CK2 (formerly casein kinase II), which phosphorylates HDAC6 at position 458 (Ser 458 ) to enhance the formation and clearance of aggresomes [39].…”