Abstract
Aurora-A is a serine/threonine kinase that plays critical roles in centrosome maturation, spindle dynamics, and chromosome orientation and it is frequently over-expressed in human cancers. In this work, we show that Aurora-A interacts with the SUMO-conjugating enzyme UBC9 and co-localizes with SUMO1 in mitotic cells. Aurora-A can be SUMOylated in vitro and in vivo. Mutation of the highly conserved SUMOylation residue lysine 249 significantly disrupts Aurora-A SUMOylation and mitotic defects characterized by defective and multipolar spindles ensue. The Aurora-AK249R mutant has normal kinase activity but displays altered dynamics at the mitotic spindle. In addition, ectopic expression of the Aurora-AK249R mutant results in a significant increase in susceptibility to malignant transformation induced by the Ras oncogene. These data suggest that modification by SUMO residues may control Aurora-A function at the spindle and that deficiency of SUMOylation of this kinase may have important implications for tumor development.
Highlights
Aurora-A is a serine/threonine kinase with important functions in the biology of centrosomes and chromosomes
Among the three Aurora kinases, over-expression of Aurora-A in human cancer was first described in primary breast and colon tumor cells (Sen et al, 1997; Bischoff et al, 1998)
Aurora-A has been found to be amplified in a subset of human tumors, and was localized to an amplicon associated with poor prognosis in patients with breast and colon tumors (20q13; Bischoff et al, 1998; Royce et al, 2004)
Summary
Aurora-A is a serine/threonine kinase with important functions in the biology of centrosomes and chromosomes This protein belongs to the Aurora kinase family composed of Aurora-A, -B, and -C in mammals (Carmena and Earnshaw, 2003). Despite their sequence similarity, the three mammalian Aurora family members differ in their expression patterns, sub-cellular localization, timing of activity, and roles in cancer development and progression. The three mammalian Aurora family members differ in their expression patterns, sub-cellular localization, timing of activity, and roles in cancer development and progression Dysfunction of these kinases has been associated with defects in the chromosome content of cells that contribute to genetic instability. All these results have aroused interest in Aurora-A as a putative oncogene and as an attractive anti-tumoral therapeutic target (Katayama et al, 2003; Perez De Castro et al, 2008; Lens et al, 2010)
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