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A Simple Method to Identify Kinases That Regulate Embryonic Stem Cell Pluripotency by High-throughput Inhibitor Screening
Published on: May 12, 2017
Reconciling the different roles of Gsk3β in "naïve" and "primed" pluripotent stem cells
Amar M Singh1, Matthew Bechard, Keriayn Smith
1Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, Athens, GA, USA.
Abstract:
Signaling pathways orchestrated by PI3K/Akt, Raf/Mek/Erk and Wnt/β-catenin are known to play key roles in the self-renewal and differentiation of pluripotent stem cells. The serine/threonine protein kinase Gsk3β has roles in all three pathways, making its exact function difficult to decipher. Consequently, conflicting reports have implicated Gsk3β in promoting self-renewal, while others suggest that it performs roles in the activation of differentiation pathways. Different thresholds of Gsk3β activity also have different biological effects on pluripotent cells, making this situation even more complex. Here, we describe a further level of complexity that is most apparent when comparing "naïve" murine and "primed" human pluripotent stem cells. In naïve cells, Gsk3β activity is restrained by PI3K/Akt, but when released from inhibitory signals it antagonizes self-renewal pathways by targeting pluripotency factors such as Myc and Nanog. This situation also applies in primed cells, but, in addition, a separate pool of Gsk3β is required to suppress canonical Wnt signaling. These observations suggest that different Gsk3β-protein complexes shift the balance between naïve and primed pluripotent cells and identify fundamental differences in their cell signaling. Altogether, these findings have important implications for the mechanisms underpinning the establishment of different pluripotent cell states and for the control of self-renewal and differentiation.
Insights
Glycogen synthase kinase 3 beta (Gsk3β) has distinct roles in regulating pluripotent stem cell states. Its activity level and protein complexes dictate whether cells self-renew or differentiate, impacting naïve and primed cell signaling.
Area of Science:
- Stem cell biology
- Cell signaling
- Molecular pathways
Background:
- Pluripotent stem cells (PSCs) self-renewal and differentiation are governed by key signaling pathways like PI3K/Akt, Raf/Mek/Erk, and Wnt/β-catenin.
- Glycogen synthase kinase 3 beta (Gsk3β) is implicated in all three pathways, leading to conflicting reports on its function in PSCs.
- Gsk3β activity thresholds influence PSC behavior, adding complexity to its role.
Purpose of the Study:
- To elucidate the complex role of Gsk3β in regulating naïve and primed pluripotent stem cell states.
- To investigate how Gsk3β activity and protein complexes differentiate between murine and human PSC signaling.
- To understand the fundamental differences in cell signaling that establish distinct pluripotent cell states.
Main Methods:
- Comparative analysis of Gsk3β activity in naïve murine and primed human pluripotent stem cells.
- Investigation of Gsk3β interactions with pluripotency factors (e.g., Myc, Nanog).
- Assessment of Gsk3β's role in regulating PI3K/Akt and Wnt/β-catenin signaling pathways.
Main Results:
- In naïve PSCs, Gsk3β antagonizes self-renewal by targeting Myc and Nanog when released from PI3K/Akt inhibition.
- In primed PSCs, Gsk3β not only targets pluripotency factors but also suppresses canonical Wnt signaling.
- Distinct Gsk3β-protein complexes are crucial for maintaining the balance between naïve and primed pluripotent states.
Conclusions:
- Gsk3β plays a critical, state-dependent role in controlling pluripotent stem cell self-renewal and differentiation.
- Differences in Gsk3β regulation and function highlight fundamental distinctions between naïve and primed PSCs.
- Understanding Gsk3β's complex roles is vital for controlling PSC states and their differentiation potential.
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