A cancer-associated aurora A mutant is mislocalized and misregulated due to loss of interaction with TPX2.
J Biol Chem
; 284(48): 33177-84, 2009 Nov 27.
Article
em En
| MEDLINE
| ID: mdl-19801554
ABSTRACT
Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction with TPX2, and deciphered the structural basis of the disruption at 2.5 A resolution. Previous studies have shown that disruption of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the loss of regulated interactions between Aurora A and its protein partners.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
/
Proteínas Serina-Treonina Quinases
/
Proteínas de Ciclo Celular
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Proteínas Associadas aos Microtúbulos
/
Mutação
/
Neoplasias
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Reino Unido