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 K. Maciver, Anagha Joshi, Michael Clinton, Luke H. Chamberlain, Austin Smith, Tom Burdon

Research output: Contribution to journalArticle

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.
LanguageEnglish
Number of pages13
JournalJournal of Cell Science
Early online date28 Aug 2018
DOIs
Publication statusPublished - 20 Sep 2018

Fingerprint

Leukemia Inhibitory Factor
Embryonic Stem Cells
Phosphatidylinositol 3-Kinases
Proteins
Lipoylation
Food
Membranes
Cell Survival
Protein Isoforms
Transcription Factors
Cell Membrane
Cytokines
Growth

Keywords

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

Cite this

Sutherland, L., Ruhe, M., Gattegno-Ho, D., Mann, K., Greaves, J., Koscielniak, M., ... Burdon, T. (2018). LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein. Journal of Cell Science. https://doi.org/10.1242/jcs.222257
Sutherland, Linda ; Ruhe, Madeleine ; Gattegno-Ho, Daniela ; Mann, Karanjit ; Greaves, Jennifer ; Koscielniak, Magdalena ; Meek, Stephen ; Lu, Zen ; Waterfall, Martin ; Taylor, Ryan ; Tsakiridis, Anestis ; Brown, Helen ; Maciver, Sutherland K. ; Joshi, Anagha ; Clinton, Michael ; Chamberlain, Luke H. ; Smith, Austin ; Burdon, Tom. / LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein. In: Journal of Cell Science. 2018.
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Sutherland, L, Ruhe, M, Gattegno-Ho, D, Mann, K, Greaves, J, Koscielniak, M, Meek, S, Lu, Z, Waterfall, M, Taylor, R, Tsakiridis, A, Brown, H, Maciver, SK, Joshi, A, Clinton, M, Chamberlain, LH, Smith, A & Burdon, T 2018, 'LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein' Journal of Cell Science. https://doi.org/10.1242/jcs.222257

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

In: Journal of Cell Science, 20.09.2018.

Research output: Contribution to journalArticle

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T1 - LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein

AU - Sutherland, Linda

AU - Ruhe, Madeleine

AU - Gattegno-Ho, Daniela

AU - Mann, Karanjit

AU - Greaves, Jennifer

AU - Koscielniak, Magdalena

AU - Meek, Stephen

AU - Lu, Zen

AU - Waterfall, Martin

AU - Taylor, Ryan

AU - Tsakiridis, Anestis

AU - Brown, Helen

AU - Maciver, Sutherland K.

AU - Joshi, Anagha

AU - Clinton, Michael

AU - Chamberlain, Luke H.

AU - Smith, Austin

AU - Burdon, Tom

PY - 2018/9/20

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N2 - 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.

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KW - Gab1

KW - embryonic stem cells

KW - palmitoylation

KW - stem cell survival

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U2 - 10.1242/jcs.222257

DO - 10.1242/jcs.222257

M3 - Article

JO - Journal of Cell Science

T2 - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

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