title: Lanthionine synthetase C-like protein 2 (LanCL2) is a novel regulator of Akt.
abstract: The serine/threonine protein kinase Akt controls a wide range of biochemical and cellular processes under the modulation of a variety of regulators. In this study, we identify the lanthionine synthetase C-like 2 (LanCL2) protein as a positive regulator of Akt activation in human liver cells. LanCL2 knockdown dampens serum- and insulin-stimulated Akt phosphorylation, whereas LanCL2 overexpression enhances these processes. Neither insulin receptor phosphorylation nor the interaction between insulin receptor substrate and phosphatidylinositide 3-kinase (PI3K) is affected by LanCL2 knockdown. LanCL2 also does not function through PP2A, a phosphatase of Akt. Instead, LanCL2 directly interacts with Akt, with a preference for inactive Akt. Moreover, we show that LanCL2 also binds to the Akt kinase mTORC2, but not phosphoinositide-dependent kinase 1. Whereas LanCL2 is not required for the Akt-mTORC2 interaction, recombinant LanCL2 enhances Akt phosphorylation by target of rapamycin complex 2 (mTORC2) in vitro. Finally, consistent with a function of Akt in regulating cell survival, LanCL2 knockdown increases the rate of apoptosis, which is reversed by the expression of a constitutively active Akt. Taken together, our findings reveal LanCL2 as a novel regulator of Akt and suggest that LanCL2 facilitates optimal phosphorylation of Akt by mTORC2 via direct physical interactions with both the kinase and the substrate.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
authors.forename: Min
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801 jiechen@illinois.edu vddonk@illinois.edu.
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801 jiechen@illinois.edu vddonk@illinois.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D002461:Cell Line, Transformed; D002470:Cell Survival; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D028044:Phosphate-Binding Proteins; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013440:Sulfides / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C471704:LANCL2 protein, human; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D028044:Phosphate-Binding Proteins; D013440:Sulfides; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C001520:lanthionine; D000409:Alanine