title: IKK interacts with rictor and regulates mTORC2.
abstract: mTORC2, the mammalian target of rapamycin complex 2 is activated by upstream growth factors, and performs two major functions, phosphorylation of AKT at the serine of 473 and cell cycle-dependent organization of actin cytoskeleton. However, the mechanisms through which mTORC2 is triggered by these signals remain unclear. We demonstrated, for the first time, that inhibitor of nuclear factor κ-B kinase (IKK) interacted with rictor and regulated mTORC2 activity. Not only endogenously, but ectopically expressed IKK α and IKK β physically interacted with rictor. An in vitro binding assay revealed that rictor interacted with IKKα and IKKβ from amino acids 999 to 1397. Moreover, chemical inhibition of IKK, knockdown of IKK by small interference RNA (siRNA), or ectopic expression of kinase-dead IKK (IKK KD) repressed phosphorylation of AKT (S473) in a variety of cell lines and decreased the kinase activity of mTORC2. In NIH 3T3 cells, inhibition of IKK also reduced phosphorylation of protein kinase α (PKCα) (S657) and resulted in disorganization of actin cytoskeleton. Interestingly, the interaction between IKKα/β and rictor was increased, while the mTOR-rictor association was attenuated by inhibition of IKK. We identified a novel signaling mechanism for the regulation of mTORC2 by IKK: IKK interacted with rictor and regulated the function of mTORC2 including phosphorylation of AKT (S473) and organization of actin cytoskeleton. Inactivated IKK interacted with rictor and competed against mTOR, which resulted in a reduced mTORC2 level and a decrease in mTORC2 activity.
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yuanfei
authors.initials: Y
authors.lastname: Xu
authors.forename: Eryong
authors.initials: E
authors.lastname: Lai
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.forename: Cuilan
authors.initials: C
authors.lastname: Yang
authors.forename: Chunhong
authors.initials: C
authors.lastname: Jia
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Bai
authors.forename: Ming
authors.initials: M
authors.lastname: Li
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; C492571:RICTOR protein, human; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human
keywords: Rictor; The IκB kinase; The mammalian target of rapamycin complex 2