Sasai Kaori, Katayama Hiroshi, Hawke David H, Sen Subrata
Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2016 Jun 22;11(6):e0157305. doi: 10.1371/journal.pone.0157305. eCollection 2016.
Aurora-C, a member of the Aurora kinase family that can complement Aurora-B function in mitosis is either moderately expressed or repressed in most adult somatic tissues but is active in early embryonic development and expressed at elevated levels in multiple human cancers. Aurora-C overexpression reportedly plays a role in tumorigenic transformation. We performed detailed characterization of Aurora-C interactions with members of the Chromosome Passenger Complex (CPC), Survivin and Inner Centromere Protein (INCENP) in reference to known Aurora-B interactions to understand the functional significance of Aurora-C overexpression in human cancer cells. The results revealed that silencing of Aurora-C or -B individually does not affect localization of the other kinase and the two kinases exist predominantly in independent complexes in vivo. Presence of Aurora-C and -B in molecular complexes of varying as well as overlapping sizes and co-existence in INCENP overexpressing cells indicated oligomerization of ternary complexes under different physiological conditions in vivo. Furthermore, Aurora-C and -B stabilized INCENP through interaction with and phosphorylation of the IN box domain while Aurora-C was activated following Survivin phosphorylation on Serine 20. Phosphorylation of Survivin residue Serine 20 by Aurora-C and -B appears important for proper chromosome segregation. Taken together, our study suggests that Aurora-C, expressed at low levels in somatic cells, functions as a catalytic component of the CPC together with Aurora-B through mitosis. Elevated expression of Aurora-C in cancer cells alters the structural and functional characteristics of the Aurora-B-CPC leading to chromosomal instability.
极光激酶C（Aurora-C）是极光激酶家族的成员之一，在有丝分裂中可补充极光激酶B的功能。在大多数成人体细胞组织中，它要么适度表达，要么受到抑制，但在早期胚胎发育中具有活性，并且在多种人类癌症中高表达。据报道，极光激酶C的过表达在肿瘤发生转化中起作用。我们参照已知的极光激酶B的相互作用，对极光激酶C与染色体乘客复合体（CPC）成员、生存素（Survivin）和着丝粒内蛋白（INCENP）之间的相互作用进行了详细表征，以了解极光激酶C在人类癌细胞中过表达的功能意义。结果显示，单独沉默极光激酶C或极光激酶B并不影响另一种激酶的定位，并且这两种激酶在体内主要存在于独立的复合体中。在大小不同以及有重叠的分子复合体中存在极光激酶C和极光激酶B，并且在过表达INCENP的细胞中共存，这表明三元复合体在体内不同生理条件下会发生寡聚化。此外，极光激酶C和极光激酶B通过与IN盒结构域相互作用并使其磷酸化来稳定INCENP，而在生存素丝氨酸20位点发生磷酸化后，极光激酶C被激活。极光激酶C和极光激酶B对生存素丝氨酸20位点的磷酸化似乎对正确的染色体分离很重要。综上所述，我们的研究表明，在体细胞中低水平表达的极光激酶C在有丝分裂过程中与极光激酶B一起作为CPC的催化成分发挥作用。癌细胞中极光激酶C的高表达改变了极光激酶B - CPC的结构和功能特性，导致染色体不稳定。
