ReviewGSK3, a master switch regulating cell-fate specification and tumorigenesis
Introduction
The cytoplasmic serine/threonine protein kinase GSK3 (glycogen synthase kinase 3) was first described in a metabolic pathway for glycogen synthase regulation that is sensitive to insulin-mediated inhibition [1]. Recently, however, GSK3 was rediscovered as a key developmental component in metazoan pattern formation and in tumorigenesis, where fate decisions were suggested to depend upon either the presence or absence of kinase activity. In this role, the spatial restriction of either active or inhibited GSK3 is required to establish dorsal–ventral axes in vertebrates, anterior–posterior segment polarity in Drosophila, animal–vegetal patterns in sea urchin, and endoderm/mesoderm or prestalk/prespore cell fates in Caenorhabditis elegans and Dictyostelium, respectively. Once thought of as a simple on-off switch, GSK3 is now envisioned as part of an integrated circuit that processes upstream signals in various cellular contexts and whereas inhibition of constitutively activated GSK3 had been the paradigm, it is now appreciated that GSK3 regulation involves activating and inhibiting mechanisms, scaffolding complexes, and the differential recognition of target substrates. The molecular details of these mechanisms had been elusive but recent studies shed new insight into the understanding of the regulation of GSK3 and its role in cell-fate decisions.
In this review, we focus on novel regulatory circuits essential for GSK3 function in cell-fate specification and in tumorigenesis. GSK3 is a versatile switch that can be selective in target discrimination and pathway insulation. Contrary to the canonical inhibitory network, several recent studies highlight an activating pathway for GSK3 in developmental pattern formation. We also address the differential assembly of GSK3 complexes in the context of substrate association.
Section snippets
Multi-protein complexes dictate GSK3 regulation
Genetic analyses of Drosophila predict a negative regulatory linkage between the secreted morphogen wingless (Wg) and the protein kinase GSK3 during development [2]. The fundamental pattern of segment polarity in Drosophila, as exemplified by alternating regions of naked bands and denticle belts in the cuticle, is established during early embryogenesis. Loss-of-function (LOF) mutations of Drosophila GSK3 (shaggy, zeste-white 3) eliminate denticle belts, whereas LOF mutations of wg (or
Activating pathways for GSK3 in C. elegans
In contrast to the inhibitory Wnt/Wg pathway for GSK3 in fate choices in Drosophila and vertebrates, endoderm induction in C. elegans requires a positive regulatory path for GSK3 (see Figure 2). The EMS cell of the 4-cell blastomere divides asymmetrically into the mesodermal MS precursor and the endodermal E precursor. Endoderm induction requires intercellular signaling from the neighboring P2 cell. Disruption of mom-2 (wg), mom-5 (fz), or GSK3 gene function results in a common ‘mom’ (more
The Yin and Yang of Dictyostelium
Studies from Dictyostelium have brought exciting new information on GSK3-mediated pattern formation (see Figure 2). Dictyostelium grow as individual amoeboid cells in the presence of an abundant food source but when nutrient levels become depleted, cells initiate a synchronous program of aggregation, forming a multicellular organism with an initial anterior/posterior body axis. In Dictyostelium, secreted cAMP serves as both a chemoattractant to mediate aggregation but also as a morphogen to
GSK3 is a versatile switch transmitting diverse downstream signals
A ‘canonical’ GSK3 phosphorylation site was described from analysis of a target enzyme, glycogen synthase (GS). GSK3 will phosphorylate clustered serines spaced at 4 amino acid intervals provided the most carboxy-terminal serine is pre-phosphorylated. CKII phosphorylation of S656 of GS is required for GSK3 phosphorylation at serines 640, 644, 648, and 652 [53]. Other studies identified GSK3 substrates that do not require pre-phosphorylation. These include, c-Jun, cyclin D1, Tau, and MBP 54, 55,
Conclusions
The protein kinase GSK3 is part of an ancient mechanism used to direct cell-fate specification in response to morphogen signaling in organisms as diverse as the facultative metazoan Dictyostelium, invertebrates, and vertebrates (Figure 2). In the simplest view, GSK3 functions as an on-off switch, but recent biochemical and genetic studies have revealed novel insights into the complexity and diversity of GSK3 regulation and function. In Dictyostelium, signal response leads to an acute alteration
Update
In contrast to what might have been anticipated, GSK3β does not appear to be required for normal axis formation in mammals [68••]. Mice deficient for GSK3 show no developmental abnormalities prior to embryonic day 12.5 (E12.5) and no apparent defects in Wnt signaling or β-catenin accumulation. Potentially, the related kinase GSK3α serves to functionally substitute during early development. Viability of these mice is eventually lost between E13.5 and E14.5. This most likely results from failure
Acknowledgements
We are indebted to Adrian Harwood for continued collaboration and generosity in sharing unpublished data and also appreciate the many thoughtful discussions with Joe Brzostowski, Lisa Kreppel, and Jingchun Liu.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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