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

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

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Abstract

The cytokine leukaemia inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESCs) 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 naive-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.

Original language	English
Article number	jcs222257
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 - 20 Sept 2018
Externally published	Yes

Bibliographical note

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

Keywords

Leukaemia inhibitory factor
Gab1
Embryonic stem cells
Palmitoylation
Stem cell survival

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10.1242/jcs.222257Licence: CC BY

PublishedFinal published version, 7.77 MBLicence: CC BY

Jennifer Greaves, PhD
- Centre for Health and Life Sciences - Associate Professor in Cell Biology
Person: Teaching and Research

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. K., 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 jcs222257. https://doi.org/10.1242/jcs.222257

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, vol. 131, no. 18, jcs222257. https://doi.org/10.1242/jcs.222257

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abstract = "The cytokine leukaemia inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESCs) 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 naive-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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AU - Tsakiridis, Anestis

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AU - Maciver, Sutherland K

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AU - Chamberlain, Luke H

AU - Smith, Austin

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N1 - This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

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N2 - The cytokine leukaemia inhibitory factor (LIF) promotes self-renewal of mouse embryonic stem cells (ESCs) 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 naive-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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ER -

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

Abstract

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Keywords

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Jennifer Greaves, PhD

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