title: PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer.
abstract: Aurora A kinase is overexpressed in the majority of breast carcinomas. A chemical genetic approach was used to identify the malignant targets of Aurora A, which revealed pleckstrin-homology-like domain protein PHLDA1 as an Aurora A substrate. PHLDA1 downregulation is a powerful prognostic predictor for breast carcinoma, which was confirmed in our study. We further show that downregulation of PHLDA1 is associated with estrogen receptor (ER) expression in breast carcinoma. Aurora A directly phosphorylates PHLDA1 leading to its degradation. PHLDA1 also negatively regulates Aurora A, thereby triggering a feedback loop. We demonstrate the underlying mechanisms by which PHLDA1 upregulation strongly antagonizes Aurora-A-mediated oncogenic pathways, thereby revealing PHLDA1 degradation as a key mechanism by which Aurora A promotes breast malignancy. Thus, not surprisingly, PHLDA1 upregulation acts synergistically with Aurora A inhibition in promoting cell death. PHLDA1 overexpression might therefore be an alternative method to modulate Aurora A deregulation in breast carcinoma. Finally, this study led to the discovery of a mutation in the Aurora A active site that renders it amenable to the chemical genetic approach. Similar mutations are required for Aurora B, suggesting that this modified approach can be extended to other kinases that have hitherto not been amenable to this methodology.
authors.affiliation: Department of Chemistry and Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Emmanuel O
authors.initials: EO
authors.lastname: Johnson
authors.forename: Kuei-Hua
authors.initials: KH
authors.lastname: Chang
authors.forename: Yolanda
authors.initials: Y
authors.lastname: de Pablo
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Rutika
authors.initials: R
authors.lastname: Mehta
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
mesh_terms: D017209:Apoptosis / Q000235:genetics; D064107:Aurora Kinase B; D064127:Aurora Kinases; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D015202:Protein Engineering; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C491923:PHLDA1 protein, human; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014157:Transcription Factors; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases