AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

Abstract

Activity of AURKA is controlled through multiple mechanisms including phosphorylation, ubiquitinmediated degradation, and allosteric interaction with TPX2. Activity peaks at mitosis before AURKA is degraded during mitotic exit in a process strictly dependent on APC/C coactivator FZR1. We used FZR1 knockout cells (FZR1 KO ) and a novel FRET-based AURKA biosensor to investigate how activity is regulated in absence of destruction. We found that AURKA activity in FZR1 KO cells dropped at mitotic exit as rapidly as in parental cells, despite absence of destruction. Unexpectedly, TPX2 was degraded normally in FZR1 KO cells. Overexpression of an N-terminal TPX2 fragment sufficient for AURKA binding, but not degraded at mitotic exit, caused delay in AURKA inactivation. We conclude that AURKA inactivation in mitotic exit is determined not by its own degradation but by degradation of TPX2 and therefore dependent on CDC20 rather than FZR1. The biosensor revealed that FZR1 instead suppresses AURKA activity in interphase and is critically required for assembly of the interphase mitochondrial network after mitosis.

A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

“…[ 59 ] However, dAurA383 treatment induces stemness related processes such as “CONRAD stem cell,” which is consistent with our finding that dAurA383 induces a population of CD34 high stem cells. dAurA450 treatment suppresses the stemness related processes such as “hallmark MYC/E2F targets,” “EPPERT Progenitor,” “WONG Embryonic stem cell core,” and “Oxidative phosphorylation,” supporting previous studies that interphase AURKA facilitates stem‐cell‐like phenotypes [ 22–24 ] and increases energy production, [ 45,46 ] and in line with that dAurA450 induces CD34 low cells and suppresses the expression of stem cell markers including c‐Myc, NANOG, STAT5A, and FOXM1. The stemness inhibition may also explain the result that dAurA450 delays the cell division but not obviously changes the cell cycle phase distribution.…”

“…The process of “oxidative phosphorylation” is enriched in dAurA450 treated cells (Figure 3D), supporting the emerging functions of interphase AURKA in mitochondrial dynamics and energy production. [ 45,46 ]…”