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Here we first showed that the LIF\/STAT3-regulated signaling pathway contributes to the maintenance of self-renewal and pluripotency of mouse ESCs by suppressing mTOR (mammalian target of rapamycin), which is necessary for early differentiation. When LIF is withdrawn from culture medium, the mTOR activity rapidly increases as detected by phosphorylation of its targets \u2013 ribosomal protein S6 and translation factor 4EBP1. In turn, suppression of STAT3 phosphorylation on Tyr-705 by a specific small molecule WP1066 also activates phosphorylation of the mTOR target S6 ribosomal protein. LIF removal strongly activates ERK activity indicating that ERK can be involved in either direct phosphorylation of mTOR or phosphorylation of an upstream negative regulator of mTOR \u2013 TSC1\/TSC2 proteins. According to western blotting data, LIF withdrawal leads to phosphorylation of TSC2 protein thereby relieving its negative effect on mTOR activity. mTOR activation is accompanied by a decrease of pluripotent gene expression <jats:italic>Oct-4, Nanog, Sox2<\/jats:italic> and by an augmentation of <jats:italic>fgf5<\/jats:italic> gene expression \u2013 a marker of post-implantation epiblast. Together, these data indicate that LIF-depleted mouse ESCs undergo a transition from the LIF\/STAT3-supported pluripotent state to the FGFR\/ERK-committed primed-like state with expression of early differentiation markers mediated through activation of mTOR signaling.<\/jats:p>","DOI":"10.1038\/cddis.2015.387","type":"journal-article","created":{"date-parts":[[2016,1,18]],"date-time":"2016-01-18T14:06:56Z","timestamp":1453126016000},"page":"e2050-e2050","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Leukemia inhibitory factor (LIF) withdrawal activates mTOR signaling pathway in mouse embryonic stem cells through the MEK\/ERK\/TSC2 pathway"],"prefix":"10.1038","volume":"7","author":[{"given":"M Y","family":"Cherepkova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G S","family":"Sineva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V A","family":"Pospelov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,14]]},"reference":[{"key":"BFcddis2015387_CR1","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/336688a0","volume":"336","author":"AG Smith","year":"1988","unstructured":"Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M et al. 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