title: Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways.
abstract: Carboxy-terminal modulator protein (CTMP) was identified as binding to the carboxy terminus of Akt and inhibiting the phosphorylation and activation of Akt. In contrast to a previous study, we found CTMP overexpression to significantly enhance Akt phosphorylation at both Thr(308) and Ser(473) as well as the kinase activity of Akt, while phosphatidylinositol 3-kinase (PI3-kinase) activity was unaffected. Translocation of Akt to the membrane fraction was also markedly increased in response to overexpression of CTMP, with no change in the whole cellular content of Akt. Furthermore, the phosphorylations of GSK-3beta and Foxo1, well-known substrates of Akt, were increased by CTMP overexpression. On the other hand, suppression of CTMP with small interfering RNA partially but significantly attenuated this Akt phosphorylation. The cellular activities reportedly mediated by Akt activation were also enhanced by CTMP overexpression. UV-B-induced apoptosis of HeLa cells was significantly reversed not only by overexpression of the active mutant of Akt (myr-Akt) but also by that of CTMP. Increases in glucose transport activity and glycogen synthesis were also induced by overexpression of either myr-Akt or CTMP in 3T3-L1 adipocytes. Taking these results into consideration, it can be concluded that CTMP induces translocation of Akt to the membrane and thereby increases the level of Akt phosphorylation. As a result, CTMP enhances various cellular activities that are principally mediated by the PI3-kinase/Akt pathway.
authors.affiliation: Department of Endocrinology and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Tokyo.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Ono
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Motonobu
authors.initials: M
authors.lastname: Anai
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Takehide
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.forename: Nanao
authors.initials: N
authors.lastname: Horike
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Uchijima
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D019556:COS Cells; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000096:biosynthesis*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013869:Thiolester Hydrolases; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose; D006003:Glycogen; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D013869:Thiolester Hydrolases; C085126:FOXO1 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C437985:THEM4 protein, human