Rapid calcium-dependent activation of Aurora-A kinase.
Oncogenic hyperactivation of the mitotic kinase Aurora-A (AurA) in cancer is associated with genomic instability. Increasing evidence indicates that AurA also regulates critical processes in normal interphase cells, but the source of such activity has been obscure. We report here that multiple stimuli causing release of Ca(2+) from intracellular endoplasmic reticulum stores rapidly and transiently activate AurA, without requirement for second messengers. This activation is mediated by direct Ca(2+)-dependent calmodulin (CaM) binding to multiple motifs on AurA. On the basis of structure-function analysis and molecular modelling, we map two primary regions of CaM-AurA interaction to unfolded sequences in the AurA N- and C-termini. This unexpected mechanism for AurA activation provides a new context for evaluating the function of AurA and its inhibitors in normal and cancerous cells.
Plotnikova
Olga V
OV
Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111, USA.
Pugacheva
Elena N
EN
Dunbrack
Roland L
RL
Golemis
Erica A
EA
D000595:Amino Acid Sequence; D000818:Animals; D064127:Aurora Kinases; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D002147:Calmodulin; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D002118:Calcium