Increased Aurora B expression reduces substrate phosphorylation and induces chromosomal instability

Abstract

Increased Aurora B protein expression, which is common in cancers, is expected to increase Aurora B kinase activity, yielding elevated phosphorylation of Aurora B substrates. In contrast, here we show that elevated expression of Aurora B reduces phosphorylation of six different Aurora B substrates across three species and causes defects consistent with Aurora B inhibition. Complexes of Aurora B and its binding partner INCENP autophosphorylate in trans to achieve full Aurora B activation. Increased expression of Aurora B mislocalizes INCENP, reducing the local concentration of Aurora B:INCENP complexes at the inner centromere/kinetochore. Co-expression of INCENP rescues Aurora B kinase activity and mitotic defects caused by elevated Aurora B. However, INCENP expression is not elevated in concert with Aurora B in breast cancer, and increased expression of Aurora B causes resistance rather than hypersensitivity to Aurora B inhibitors. Thus, increased Aurora B expression reduces, rather than increases, Aurora B kinase activity.

Double-checking chromosome segregation

“…This knowledge will be necessary to understand how a midzone Aurora B activity gradient mediates anaphase error correction and to test whether similar mechanisms operate during meiosis. Moreover, because Aurora B is overexpressed in highly aneuploid cancers ( Pfister et al, 2018 ; Smith et al, 2005 ; Takeshita et al, 2013 ) and its overexpression was recently shown to inhibit Aurora B activity toward different kinetochore substrates ( Britigan et al, 2022 ), it will be important to investigate whether anaphase surveillance and error correction mechanisms are disrupted in human cancers.…”