title: LIMK2 is a crucial regulator and effector of Aurora-A-kinase-mediated malignancy.
abstract: Aurora A is overexpressed in majority of breast carcinomas. With the exception of BRCA1 and PHLDA1, no oncogenic Aurora A substrates are known in breast cancer. In this study, a chemical genetic approach was used to identify malignant targets of Aurora A, which revealed LIMK2 as a novel Aurora A substrate. Aurora A regulates LIMK2 kinase activity, subcellular localization and protein levels by direct phosphorylation at S283, T494 and T505. In response, LIMK2 also positively regulates the level of Aurora A, thereby engaging in a positive-feedback loop, promoting Aurora-A-mediated oncogenic pathways. Most importantly, LIMK2 ablation fully abrogates Aurora-A-mediated tumorigenesis in nude mice, suggesting that LIMK2 is a key oncogenic effector of Aurora A. Furthermore, LIMK2 ablation acts synergistically with inhibition of Aurora A in promoting cell death. Finally, Aurora-A-mediated upregulation of LIMK2 appears to be a common mechanism in many cancers. LIMK2 inhibition or ablation is therefore an alternative approach for modulating Aurora A deregulation in cancer.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, 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: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Chelvam
authors.initials: C
authors.lastname: Venkatesh
authors.forename: Katie
authors.initials: K
authors.lastname: Giger
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
mesh_terms: D000818:Animals; D017209:Apoptosis; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D054461:Lim Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014183:Transplantation, Heterologous
chemical_list: D034741:RNA, Small Interfering; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; C102895:LIMK2 protein, human; D054461:Lim Kinases; D017346:Protein Serine-Threonine Kinases