title: Calmodulin activation of Aurora-A kinase (AURKA) is required during ciliary disassembly and in mitosis.
abstract: The centrosomal Aurora-A kinase (AURKA) regulates mitotic progression, and overexpression and hyperactivation of AURKA commonly promotes genomic instability in many tumors. Although most studies of AURKA focus on its role in mitosis, some recent work identified unexpected nonmitotic activities of AURKA. Among these, a role for basal body-localized AURKA in regulating ciliary disassembly in interphase cells has highlighted a role in regulating cellular responsiveness to growth factors and mechanical cues. The mechanism of AURKA activation involves interactions with multiple partner proteins and is not well understood, particularly in interphase cells. We show here that AURKA activation at the basal body in ciliary disassembly requires interactions with Ca(2+) and calmodulin (CaM) and that Ca(2+)/CaM are important mediators of the ciliary disassembly process. We also show that Ca(2+)/CaM binding is required for AURKA activation in mitosis and that inhibition of CaM activity reduces interaction between AURKA and its activator, NEDD9. Finally, mutated derivatives of AURKA impaired for CaM binding and/or CaM-dependent activation cause defects in mitotic progression, cytokinesis, and ciliary resorption. These results define Ca(2+)/CaM as important regulators of AURKA activation in mitotic and nonmitotic signaling.
authors.affiliation: Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Plotnikova
authors.forename: Anna S
authors.initials: AS
authors.lastname: Nikonova
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Loskutov
authors.forename: Polina Y
authors.initials: PY
authors.lastname: Kozyulina
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pugacheva
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D048749:Cytokinesis; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D008938:Mitosis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002147:Calmodulin; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D002118:Calcium