cells Review GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior Claire Racaud-Sultan * and Nathalie Vergnolle IRSD, INSERM, INRAE, ENVT, Université de Toulouse, UPS, CHU Purpan, Place du Dr Baylac, CEDEX 3, 31024 Toulouse, France; [email protected] * Correspondence: [email protected] Abstract: In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent β cellular functions. GSK3 activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients. Citation: Racaud-Sultan, C.; Vergnolle, N. GSK3β, a Master Keywords: GSK3b; stem cell; integrin; PAR2 Kinase in the Regulation of Adult Stem Cell Behavior. Cells 2021, 10, 225. https://doi.org/10.3390/ cells10020225 1. Introduction Academic Editor: The Glycogen Synthase Kinase 3β (GSK3β) is an ancestral protein kinase, ubiquitously Hagit Eldar-Finkelman expressed, which controls many cellular functions [1]. Inhibited in basal conditions, GSK3β Received: 30 November 2020 is activated under stress and can drive cells to death or to survival depending on its sub- Accepted: 22 January 2021 cellular localization and specific partners. GSK3β has been found activated in pathologies Published: 24 January 2021 such as inflammation and cancer where the deregulation of adult stem cells plays a critical role [2]. Here, we will summarize some key GSK3β-dependent regulations of adult stem Publisher’s Note: MDPI stays neutral cells and their consequences on the behavior of hematopoietic and intestinal stem cells, as with regard to jurisdictional claims in examples. We will highlight the importance of adhesion and protease-activated receptors published maps and institutional affil- engagement in the activation of signaling pathways conducting to GSK3β activation. Fi- iations. nally, we will discuss the positive and negative aspects of GSK3β activation in pathological conditions and the benefit to consider GSK3β as diagnostic marker and therapeutic target for a precision medicine. β Copyright: © 2021 by the authors. 2. GSK3 as a Sensor of the Adult Stem Cell Niche Licensee MDPI, Basel, Switzerland. Adult stem cells are in charge of tissue regeneration along the life of organisms. This This article is an open access article is the reason why they must be protected from stressors leading to cell death or exhaustion. distributed under the terms and The microenvironment of adult stem cells, namely “niche”, supports this protective role conditions of the Creative Commons offering in particular an adhesive anchorage and proper metabolic exchanges [3]. However, Attribution (CC BY) license (https:// aging and exogenous aggressions decrease the niche capacities to control stem cell behavior creativecommons.org/licenses/by/ and thus favor pathogenesis. 4.0/). Cells 2021, 10, 225. https://doi.org/10.3390/cells10020225 https://www.mdpi.com/journal/cells Cells 2021, 10, 225 2 of 12 Cells 2021, 10, x FOR PEER REVIEW 2 of 12 Facing stress, adult stem cells could undergo apoptosis, or exhaustion through acceler- However,ated differentiation, aging and exogenous or senescence, aggressions ordecrease tumor the transformation. niche capacities to As control a first stem step, stem cells must cell behavior and thus favor pathogenesis. surviveFacing stress, and adult cope stem with cells nutrient could undergo or oxidative apoptosis, stress. or exhaustion Through through its strategic accel‐ locations in the eratedcell differentiation, (plasma membrane, or senescence, endoplasmic or tumor transformation. reticulum, mitochondria, As a first step, nucleus),stem cells and in response mustto survive various and signals, cope with GSK3 nutrientβ is or able oxidative to control stress. death-signaling Through its strategic pathways locations in at the membranes, the cellenergetic (plasma metabolism membrane, endoplasmic and gene reticulum, transcription mitochondria, [1]. Thus, nucleus), a resistant and in quiescentre‐ stem cell sponsephenotype to various issignals, established. GSK3 is able It is to linked control to death a strong‐signaling anchorage pathways to at the extracellular mem‐ matrix and branes,supporting energetic metabolism cells in the and niche, gene as transcription well as a low [1]. Thus, energetic a resistant metabolism quiescent [ stem4,5]. cell phenotype is established. It is linked to a strong anchorage to extracellular matrix and GSK3β acts as a key sensor of cell metabolism and its activation allows energetic supporting cells in the niche, as well as a low energetic metabolism [4,5]. supplyGSK3 acts and as anti-oxidant a key sensor of defenses cell metabolism in a low-glucose and its activation microenvironment allows energetic sup [6].‐ Indeed, in basal ply andconditions, anti‐oxidant Insulin defenses receptor-signaling in a low‐glucose complex microenvironment inhibits GSK3[6]. Indeed,β to release in basal glycogenesis and conditions,Nrf2-dependent Insulin receptor anti-oxidant‐signaling complex systems. inhibits In addition GSK3 to to release its role glycogenesis in survival and of adult stem cells, Nrf2active‐dependent GSK3 antiβ ‐preventsoxidant systems. ROS-induced In addition differentiation to its role in survival or senescence of adult stem [7 cells,]. active GSK3As recapitulatedprevents ROS‐induced in Figure differentiation1, GSK3 β orplays senescence a central [7]. role in the adaptation of adult stemAs recapitulated cells to their in Figure microenvironment 1, GSK3 plays a allowing central role their in the long-term adaptation maintenance of adult during the stem cells to their microenvironment allowing their long‐term maintenance during the wholewhole life of life the oforganism. the organism. Niche Stem cell -Extracellular matrix -Nutrient metabolites -Cytokines… PM ER GSK3 GSK3 Protein/lipid Signal metabolism transduction Mi GSK3 Nu Energy GSK3 metabolism Gene transcription RESISTANCE TO CELL DEATH QUIESCENCE ADHESION FigureFigure 1. Multiple 1. Multiple cellular cellularlocalization localization of GSK3 activation of GSK3 andβ activation consequences and on consequences stem cell status. on stem cell status. At the plasma membrane, GSK3is critical to counteract death‐signaling pathways induced by cy‐ tokinesAt and the adhesion plasma changes membrane, in injured GSK3 microenvironment.β is critical to In counteract case of nutrient death-signaling or oxidative stresses, pathways induced by GSK3cytokines can adjust and metabolic adhesion activities changes in the endoplasmic in injured microenvironment.reticulum and in mitochondria. In case Cell of sur nutrient‐ or oxidative vivalstresses, and metabolism GSK3β arecan tightly adjust linked metabolic and their activities cross‐regulation in the is endoplasmic particularly important reticulum in sub and‐ in mitochondria. cellular compartments where GSK3 is found. In the nucleus, GSK3modulated gene transcription contributesCell survival to shape andthe resistant metabolism phenotype are tightlyof stem cells. linked Localized and their signaling cross-regulation activities responsible is particularly important for GSK3in subcellular activation are compartments complex as well where as the GSK3relationshipβ is found.between them In the [1]. nucleus, PM: Plasma GSK3 memβ‐−modulated gene brane;transcription ER: Endoplasmic contributes reticulum; to Mi: shape Mitochondria; the resistant Nu: Nucleus. phenotype of stem cells. Localized signaling activities responsible for GSK3β activation are complex as well as the relationship between them [1]. PM: Plasma membrane; ER: Endoplasmic reticulum; Mi: Mitochondria; Nu: Nucleus. 3. GSK3β and Key Functions of Adult Stem Cells The implication of GSK3β activation in adult stem cell regulation has first been identified for self-renewal function. Indeed, as a serine-threonine kinase, GSK3β is able to phosphorylate β-catenin, targeting it to the proteasome for degradation and blocking its translocation to the nucleus, normally required for stem cell renewal [8]. In the nucleus, β-catenin is a partner of the transcription factor TCF which promotes self-renewal, a Cells 2021, 10, 225 3 of 12 proliferative mode maintaining tissue stem cells. Thus the activation of the GSK3β pool associated with β-catenin in the cytoplasm can push stem cells towards a quiescent state. Another important aspect of GSK3β-dependent regulation of stem cells is the control