LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein

Sutherland, Linda and Ruhe, Madeleine and Gattegno-Ho, Daniela and Mann, Karanjit and Greaves, Jennifer and Koscielniak, Magdalena and Meek, Stephen and Lu, Zen and Waterfall, Martin and Taylor, Ryan and Tsakiridis, Anestis and Brown, Helen and Maciver, Sutherland K. and Joshi, Anagha and Clinton, Michael and Chamberlain, Luke H. and Smith, Austin and Burdon, Tom (2018) LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein. Journal of Cell Science. ISSN 0021-9533

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    Abstract

    The cytokine leukaemia Inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESC) through activation of the transcription factor Stat3. However, the contribution of other ancillary pathways stimulated by LIF in ESCs, such as the MAPK and PI3K pathways, is less well understood. We show here that naïve-type mouse ESCs express high levels of a novel effector of the MAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal Pleckstrin Homology (PH) membrane-binding domain. Although not essential for rapid unrestricted growth of ESCs under optimal conditions, the novel Gab1 variant (Gab1β) is required for LIF-mediated cell survival under conditions of limited nutrient availability. This enhanced survival is absolutely dependent upon a latent palmitoylation site that targets Gab1β directly to ESC membranes. These results show that constitutive association of Gab1 with membranes through a novel mechanism promotes LIF-dependent survival of murine ESCs in nutrient poor conditions.