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

Linda Sutherland, Madeleine Ruhe, Daniela Gattegno-Ho, Karanjit Mann, Jennifer Greaves, Magdalena Koscielniak, Stephen Meek, Zen Lu, Martin Waterfall, Ryan Taylor, Anestis Tsakiridis, Helen Brown, Sutherland Maciver, Anagha Joshi, Michael Clinton, Luke H Chamberlain, Austin Smith, Thomas Burdon

Research output: Contribution to journalArticlepeer-review

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
(Gab1) 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 Gab1 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.
Original languageEnglish
Article number222257
JournalJournal of Cell Science
Volume131
Issue number18
Early online date28 Aug 2018
DOIs
Publication statusPublished - Sep 2018

Keywords

  • Leukaemia inhibitory factor
  • Gab1
  • embryonic stem cells
  • palmitoylation
  • stem cell survival

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