title: Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture.
abstract: Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation.
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.|Stem Cells Australia, The University of Melbourne, Parkville, Australia.
authors.forename: Boon Siang Nicholas
authors.initials: BS
authors.lastname: Tan
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.|Australian Stem Cell Centre, Monash University, Clayton, Australia.
authors.forename: Joly
authors.initials: J
authors.lastname: Kwek
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.|Australian Stem Cell Centre, Monash University, Clayton, Australia.
authors.forename: Chong Kum Edwin
authors.initials: CK
authors.lastname: Wong
authors.affiliation: Menzies Institute of Medical Research, University of Tasmania, Hobart, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Saner
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Yap
authors.affiliation: Stem Cells Australia, The University of Melbourne, Parkville, Australia.|School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Felquer
authors.affiliation: Australian Stem Cell Centre, Monash University, Clayton, Australia.|School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Morris
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.|Stem Cells Australia, The University of Melbourne, Parkville, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Gardner
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.|Australian Stem Cell Centre, Monash University, Clayton, Australia.|Menzies Institute of Medical Research, University of Tasmania, Hobart, Australia.|School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Rathjen
authors.affiliation: School of BioSciences, University of Melbourne, Parkville, Australia.|Stem Cells Australia, The University of Melbourne, Parkville, Australia.|Australian Stem Cell Centre, Monash University, Clayton, Australia.|School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.|School of Medicine, University of Tasmania, Hobart, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Rathjen
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000201:enzymology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases