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

doi:10.1242/jcs.222257

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 journal › Article › peer-review

Abstract / Description of output

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 language	English
Article number	222257
Journal	Journal of Cell Science
Volume	131
Issue number	18
Early online date	28 Aug 2018
DOIs	https://doi.org/10.1242/jcs.222257
Publication status	Published - Sept 2018

Keywords / Materials (for Non-textual outputs)

Leukaemia inhibitory factor
Gab1
embryonic stem cells
palmitoylation
stem cell survival

Access to Document

10.1242/jcs.222257

jcs222257.fullFinal published version, 7.51 MBLicence: Creative Commons: Attribution (CC-BY)

ISP 2017/22-Burdon Tom
Burdon, T.
BBSRC
1/04/17 → 31/03/22
Project: Research

Tom Burdon
- tom.burdonroslin.ed.acuk
- Royal (Dick) School of Veterinary Studies - Group Leader/Senior Research Fellow
Person: Academic: Research Active

Cite this

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, S., Joshi, A., Clinton, M., Chamberlain, L. H., 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, 131(18), Article 222257. https://doi.org/10.1242/jcs.222257

@article{15de3fa55d384237ac425f18c84bc330,

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

abstract = "The cytokine leukaemia Inhibitory factor (LIF) promotes self-renewal of mouseembryonic stem cells (ESC) through activation of the transcription factor Stat3.However, the contribution of other ancillary pathways stimulated by LIF inESCs, such as the MAPK and PI3K pathways, is less well understood. We showhere that na{\"i}ve-type mouse ESCs express high levels of a novel effector of theMAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal PleckstrinHomology (PH) membrane-binding domain. Although not essential for rapidunrestricted growth of ESCs under optimal conditions, the novel Gab1 variant(Gab1) is required for LIF-mediated cell survival under conditions of limitednutrient availability. This enhanced survival is absolutely dependent upon alatent palmitoylation site that targets Gab1 directly to ESC membranes. Theseresults show that constitutive association of Gab1 with membranes through anovel mechanism promotes LIF-dependent survival of murine ESCs in nutrientpoor conditions.",

keywords = "Leukaemia inhibitory factor, Gab1, embryonic stem cells, palmitoylation, stem cell survival",

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

year = "2018",

month = sep,

doi = "10.1242/jcs.222257",

language = "English",

volume = "131",

journal = "Journal of Cell Science",

issn = "0021-9533",

publisher = "Company of Biologists Ltd",

number = "18",

}

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, S, 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, vol. 131, no. 18, 222257. https://doi.org/10.1242/jcs.222257

TY - JOUR

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

AU - Joshi, Anagha

AU - Clinton, Michael

AU - Chamberlain, Luke H

AU - Smith, Austin

AU - Burdon, Thomas

PY - 2018/9

Y1 - 2018/9

N2 - The cytokine leukaemia Inhibitory factor (LIF) promotes self-renewal of mouseembryonic stem cells (ESC) through activation of the transcription factor Stat3.However, the contribution of other ancillary pathways stimulated by LIF inESCs, such as the MAPK and PI3K pathways, is less well understood. We showhere that naïve-type mouse ESCs express high levels of a novel effector of theMAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal PleckstrinHomology (PH) membrane-binding domain. Although not essential for rapidunrestricted growth of ESCs under optimal conditions, the novel Gab1 variant(Gab1) is required for LIF-mediated cell survival under conditions of limitednutrient availability. This enhanced survival is absolutely dependent upon alatent palmitoylation site that targets Gab1 directly to ESC membranes. Theseresults show that constitutive association of Gab1 with membranes through anovel mechanism promotes LIF-dependent survival of murine ESCs in nutrientpoor conditions.

AB - The cytokine leukaemia Inhibitory factor (LIF) promotes self-renewal of mouseembryonic stem cells (ESC) through activation of the transcription factor Stat3.However, the contribution of other ancillary pathways stimulated by LIF inESCs, such as the MAPK and PI3K pathways, is less well understood. We showhere that naïve-type mouse ESCs express high levels of a novel effector of theMAPK and PI3K pathways. This effector is an isoform of the Gab1 (Grb2-associated binder protein 1) adaptor protein that lacks the N-terminal PleckstrinHomology (PH) membrane-binding domain. Although not essential for rapidunrestricted growth of ESCs under optimal conditions, the novel Gab1 variant(Gab1) is required for LIF-mediated cell survival under conditions of limitednutrient availability. This enhanced survival is absolutely dependent upon alatent palmitoylation site that targets Gab1 directly to ESC membranes. Theseresults show that constitutive association of Gab1 with membranes through anovel mechanism promotes LIF-dependent survival of murine ESCs in nutrientpoor conditions.

KW - Leukaemia inhibitory factor

KW - Gab1

KW - embryonic stem cells

KW - palmitoylation

KW - stem cell survival

U2 - 10.1242/jcs.222257

DO - 10.1242/jcs.222257

M3 - Article

SN - 0021-9533

VL - 131

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 18

M1 - 222257

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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ISP 2017/22-Burdon Tom

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