title: Nuclear Akt2 opposes limbal keratinocyte stem cell self-renewal by repressing a FOXO-mTORC1 signaling pathway.
abstract: Signals downstream of Akt can either favor or oppose stem cell (SC) maintenance, but how this dual role can be achieved is still undefined. Using human limbal keratinocyte stem cells (LKSCs), a SC type used in transplantation therapies for corneal regeneration, we show that Akt signaling is prominent in SC populations both in vivo and in vitro, and that Akt1 promotes while Akt2 opposes SC self-renewal. Noteworthy, loss of Akt2 signaling enhances LKSC maintenance ex vivo, whereas Akt1 depletion anticipates SC exhaustion. Mechanistically, the antagonistic functions of Akt1 and Akt2 in SC control are mainly dictated by their differential subcellular distribution, being nuclear Akt2 selectively implicated in FOXO inhibition. Akt2 downregulation favors LKSC maintenance as a result of a gain of FOXO functions, which attenuates the mechanistic target of rapamycin complex one signaling via tuberous sclerosis one gene induction, and promotes growth factor signaling through Akt1. Consistently, Akt2 deficiency also enhances limbal SCs in vivo. Thus, our findings reveal distinct roles for nuclear versus cytosolic Akt signaling in normal epithelial SC control and suggest that the selective Akt2 inhibition may provide novel pharmacological strategies for human LKSC expansion in therapeutic settings and mechanistic research.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Saoncella
authors.forename: Beatrice
authors.initials: B
authors.lastname: Tassone
authors.forename: Erika
authors.initials: E
authors.lastname: Deklic
authors.forename: Fabio
authors.initials: F
authors.lastname: Avolio
authors.forename: Cristina
authors.initials: C
authors.lastname: Jon
authors.forename: Giusy
authors.initials: G
authors.lastname: Tornillo
authors.forename: Elisa
authors.initials: E
authors.lastname: De Luca
authors.forename: Enzo
authors.initials: E
authors.lastname: Di Iorio
authors.forename: Roberto
authors.initials: R
authors.lastname: Piva
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Enzo
authors.initials: E
authors.lastname: Calautti
mesh_terms: D016475:3T3 Cells; D000328:Adult; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology*; D049109:Cell Proliferation; D002999:Clone Cells; D004789:Enzyme Activation; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology*; D016850:Limbus Corneae / Q000166:cytology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007527:Isoenzymes; D046912:Multiprotein Complexes; D012097:Repressor Proteins; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494922:Akt2 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt isoforms in stratified epithelial stem cells; Akt2 knockout mice/human limbal keratinocyte stem cells; Akt2-FOXO-mTORC1 signaling in keratinocyte