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A novel interaction between Glycogen Synthase Kinase-3? (GSK-3?) and the scaffold protein Receptor for Activated C-Kinase 1 (RACK1) regulates the circadian clock.

ABSTRACT: Glycogen synthase kinase-3? (GSK-3?) and GSK-3? are intracellular kinases with largely redundant functions. However, the deletion of each GSK-3 isoform in the mouse has distinct consequences, suggesting that these related enzymes also have non-overlapping isoform-specific functions. A yeast two-hybrid screen for GSK-3? interacting partners revealed an interaction with the Receptor for Activated C-Kinase 1 (RACK1). We confirm this interaction in mammalian cells, and provide evidence that RACK1 does not interact with GSK-3?. Structure-function analyses revealed that WD repeats 5-6 are required to interact with GSK-3?. Furthermore, this interaction is independent of GSK-3? activity. Finally, our data show that the GSK-3?-RACK1 interaction is necessary for regulating the circadian clock in mammalian cells. In summary, our data provides a mechanistic link between GSK-3 and RACK-1 in the regulation of the circadian clock, and demonstrates that this effect is specific to the GSK-3? isoform.

SUBMITTER: Zeidner LC

PROVIDER: S-EPMC3242428 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A novel interaction between Glycogen Synthase Kinase-3α (GSK-3α) and the scaffold protein Receptor for Activated C-Kinase 1 (RACK1) regulates the circadian clock.

Zeidner Leigh C LC Buescher Jessica L JL Phiel Christopher J CJ

International journal of biochemistry and molecular biology 20111120 4

Glycogen synthase kinase-3α (GSK-3α) and GSK-3β are intracellular kinases with largely redundant functions. However, the deletion of each GSK-3 isoform in the mouse has distinct consequences, suggesting that these related enzymes also have non-overlapping isoform-specific functions. A yeast two-hybrid screen for GSK-3α interacting partners revealed an interaction with the Receptor for Activated C-Kinase 1 (RACK1). We confirm this interaction in mammalian cells, and provide evidence that RACK1 do ...[more]

PMID: 22187666

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Project description:Introduction: Multiple factors and pathways have been reported as critical machineries for cell differentiation and survival during pregnancy; a number of them involve glycogen synthase kinase (GSK) 3a/β. Several reports on GSK3's functional role exist; however, the specific role of GSK3 in reproductive tissues and its contribution to normal or abnormal parturition are still unclear. To fill this knowledge gap, a systematic review of literature was conducted to better understand the functional role of GSK3 in various intrauterine tissues during implantation, pregnancy, and parturition.Methods: We conducted a systematic review of literature on GSK3's expression and function reported between 1980 and 2017 in reproductive tissues during pregnancy using three electronic databases (Web of Science, Medline, and ClinicalTrials.gov). Study selection, data extraction, quality assessment and analyses were performed in duplicate by two independent reviewers.Results: A total of 738 citations were identified; 80 were selected for full text evaluation and 25 were included for final review. GSK3's regulation and function were mostly studied in tissues and cells from placentas (12), fetuses (8), uteruses (6), and ovaries (2). GSK3 is primarily reported as a downstream responder of protein kinase B (AKT)-, Wnt-, and reactive oxygen species (ROS)-related pathways where it plays a critical role in cell survival and growth in reproductive tissues.Conclusions: Though GSK3 has been functionally linked to a number of biological processes in reproductive tissues, it has primarily been studied as a secondary signaler of various conserved cell signaling pathways. Lack of scientific rigor in studying GSK3's role in reproductive tissues makes this molecule's function still obscure. No studies have reported GSK3 in the cervix, and very few reports exist in myometrium and decidua. This systematic review suggests more functional and mechanistic studies focusing on GSK3 need to be conducted in reproductive biology.

Project description:BackgroundChronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. TGF-β is a key mediator stimulating ECM production by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signalling pathways; its role in TGF-β₁-induced myofibroblast differentiation is currently largely unknown.PurposeTo determine the contribution of GSK-3 signalling in TGF-β₁-induced myofibroblast differentiation.Experimental approachWe used MRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD. Protein and mRNA expression were determined by immunoblotting and RT-PCR analysis respectively.ResultsStimulation of MRC5 and primary human lung fibroblasts with TGF-β₁ resulted in time- and dose-dependent increases of α-sm-actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition of GSK-3 by SB216763 dose-dependently attenuated TGF-β₁-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β₁-induced expression of α-sm-actin and fibronectin. The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. Neither smad, NF-κB nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast differentiation. Rather, SB216763 increased the phosphorylation of CREB, which in its phosphorylated form acts as a functional antagonist of TGF-β/smad signalling.Conclusion and implicationWe demonstrate that GSK-3 signalling regulates TGF-β₁-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases.

Dataset Information

A novel interaction between Glycogen Synthase Kinase-3? (GSK-3?) and the scaffold protein Receptor for Activated C-Kinase 1 (RACK1) regulates the circadian clock.

Publications

A novel interaction between Glycogen Synthase Kinase-3α (GSK-3α) and the scaffold protein Receptor for Activated C-Kinase 1 (RACK1) regulates the circadian clock.

Similar Datasets

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