Figure 4.

Regulation of Aurora-A and -B and control of the Warburg effect. A) Despite high-sequence similarity, Aurora-A and -B are associated with, and activated by, distinct binding partners, MYCN (PDB: 1OL5) and INCENP (PDB: 2BFX). B) Superimposition of the two kinases reveals that MYCN promotes a completely active configuration of Aurora-A, as demonstrated by the some of the structural trademarks described in Figure 1C, as well as a pAL/αC helix interaction. Conversely, INCENP promotes an intermediate state of Aurora-B activation, in which inward rotation of the αC helix physically separates relevant sidechains that typically bond within ∼3 Å (Å). C) As described in the text, both c-MYC and MYCN are ubiquitinated and degraded as a result of GSK3β phosphorylation under Akt-inhibited conditions, which can be overcome by Aurora-A binding to MYCN, and in the case c-MYC, Aurora-A inhibiting GSK3β phosphorylation by an unknown mechanism. D) Aurora-A regulates the Warburg effect that enhances cell proliferation (dependent on the utilisation of biosynthetic intermediates) by direct substrate phosphorylation and transcriptional activation through c-MYC. Aurora-A also transcriptionally regulates Aurora-B and other mitotic kinases via its interaction with MYCN, as well as ODC1, a vital enzyme in polyamine biosynthesis overexpressed in MYCN-amplified neuroblastoma.