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A cancer-associated aurora A mutant is mislocalized and misregulated due to loss of interaction with TPX2
Rachel Ann Bibby1, Chan Tang, Amir Faisal
1Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, UK.
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.
Insights
Somatic mutations in Aurora A kinase alter its activity, potentially driving cancer. The S155R mutation disrupts TPX2 interaction, leading to chromosomal abnormalities and possibly promoting aneuploidy in colon cancer.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Structural Biology
Background:
- Protein kinases, including Aurora A, are crucial in cell division and cancer development.
- Somatic mutations in Aurora A kinase can alter its function and contribute to tumorigenesis.
- The specific impact of cancer-associated Aurora A mutations on kinase activity and regulation remains largely undetermined.
Purpose of the Study:
- To investigate the functional consequences of three somatic cancer-associated mutations in the catalytic domain of Aurora A kinase.
- To characterize the Aurora A(S155R) mutant, focusing on its interaction with TPX2 and structural basis of disruption.
- To explore the potential role of Aurora A mutations in microsatellite instability-positive colon cancer.
Main Methods:
- Analysis of kinase activity for three Aurora A mutants (V174M, S155R, S361*).
- Biochemical and structural characterization of the Aurora A(S155R) mutant, including interaction studies with TPX2 and X-ray crystallography.
- Screening of colon cancer patient samples for the presence of Aurora A mutations.
Main Results:
- Aurora A(V174M) exhibited constitutively increased kinase activity.
- Aurora A(S155R) showed decreased activity due to misregulation, linked to loss of TPX2 interaction.
- Aurora A(S361*) activity was ablated due to loss of structural integrity.
- Structural analysis of Aurora A(S155R) revealed disruption of TPX2 binding at 2.5 Å resolution.
- One microsatellite instability-positive colon cancer patient sample showed exclusive presence of Aurora A(S155R) in tumor tissue.
Conclusions:
- Somatic mutations in Aurora A kinase can lead to distinct alterations in kinase activity and regulation, suggesting diverse roles in cancer.
- The S155R mutation impairs Aurora A function by disrupting its interaction with TPX2, potentially causing chromosomal abnormalities and aneuploidy.
- The S155R mutation represents a potential, albeit infrequent, driver of aneuploidy in microsatellite instability-positive colon cancer through dysregulated protein interactions.
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