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极光激酶失活突变体破坏了与 Ajuba 的相互作用，并导致 HeLa 细胞有丝分裂纺锤体形成缺陷和 G2/M 期阻滞。

Aurora-A kinase-inactive mutants disrupt the interaction with Ajuba and cause defects in mitotic spindle formation and G2/M phase arrest in HeLa cells.

机构信息

State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, People's Republic of China.

出版信息

BMB Rep. 2014 Nov;47(11):631-6. doi: 10.5483/bmbrep.2014.47.11.250.

DOI:10.5483/bmbrep.2014.47.11.250
PMID:24499673
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4281342/
Abstract

Aurora-A is a centrosome-localized serine/threonine kinase that is overexpressed in multiple human cancers. We previously reported an intramolecular inhibitory regulation of Aurora-A between its N-terminal regulatory domain (Nt, amino acids [aa] 1-128) and the C-terminal catalytic domain (Cd, aa 129-403). Here, we demonstrate that although both Aurora-A mutants (AurA-K250G and AurA-D294G/Y295G) lacked interactions between the Nt and Cd, they also failed to interact with Ajuba, an essential activator of Aurora-A, leading to loss of kinase activity. Additionally, overexpression of either of the mutants resulted in centrosome amplification and mitotic spindle formation defects. Both mutants were also able to cause G2/M arrest and apoptosis. These results indicate that both K250 and D294/Y295 are critical for direct interaction between Aurora-A and Ajuba and the function of the Aurora-A complex in cell cycle progression.

摘要

极光激酶 A 是一种定位于中心体的丝氨酸/苏氨酸激酶，在多种人类癌症中过表达。我们之前报道过极光激酶 A 的 N 端调节域（Nt，氨基酸 [aa] 1-128）和 C 端催化域（Cd，aa 129-403）之间存在分子内抑制调节。在这里，我们证明尽管 Aurora-A 的两个突变体（AurA-K250G 和 AurA-D294G/Y295G）缺乏 Nt 和 Cd 之间的相互作用，但它们也无法与 Ajuba 相互作用，Ajuba 是 Aurora-A 的必需激活剂，导致激酶活性丧失。此外，过表达任一种突变体都会导致中心体扩增和有丝分裂纺锤体形成缺陷。这两种突变体都能够引起 G2/M 期阻滞和细胞凋亡。这些结果表明 K250 和 D294/Y295 对于 Aurora-A 与 Ajuba 之间的直接相互作用以及 Aurora-A 复合物在细胞周期进程中的功能都是至关重要的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/d56b07608a26/BMB-47-631-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/7633de952d0d/BMB-47-631-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/49456e17d447/BMB-47-631-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/4d75b7cd70be/BMB-47-631-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/d56b07608a26/BMB-47-631-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/7633de952d0d/BMB-47-631-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/49456e17d447/BMB-47-631-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/4d75b7cd70be/BMB-47-631-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8917/4281342/d56b07608a26/BMB-47-631-g0004.jpg

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本文引用的文献

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Aurora A contributes to p150(glued) phosphorylation and function during mitosis.极光 A 在有丝分裂过程中有助于 p150(glued) 的磷酸化和功能。
J Cell Biol. 2010 May 17;189(4):651-9. doi: 10.1083/jcb.201001144.
2
The Aurora kinase family in cell division and cancer.细胞分裂与癌症中的极光激酶家族。
Biochim Biophys Acta. 2008 Sep;1786(1):60-72. doi: 10.1016/j.bbcan.2008.07.003. Epub 2008 Jul 23.
3
Identification of the auto-inhibitory domains of Aurora-A kinase.极光激酶A自身抑制结构域的鉴定。
RACK1 通过调节 Aurora-A 影响 G2/M 的进程。
Cell Cycle. 2019 Sep;18(18):2228-2238. doi: 10.1080/15384101.2019.1642065. Epub 2019 Jul 29.
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Issues in interpreting the in vivo activity of Aurora-A.解读极光激酶A体内活性的相关问题。
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5
P42 Ebp1 functions as a tumor suppressor in non-small cell lung cancer.P42 Ebp1在非小细胞肺癌中作为一种肿瘤抑制因子发挥作用。
BMB Rep. 2015 Mar;48(3):159-65. doi: 10.5483/bmbrep.2015.48.3.130.
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The focal adhesion scaffolding protein HEF1 regulates activation of the Aurora-A and Nek2 kinases at the centrosome.粘着斑支架蛋白HEF1在中心体调节极光激酶A和Nek2激酶的激活。
Nat Cell Biol. 2005 Oct;7(10):937-46. doi: 10.1038/ncb1309. Epub 2005 Sep 25.
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