Glycogen synthase kinase-3  is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts

Kandasamy, Arulmozhi D.; Schulz, Richard

doi:10.1093/cvr/cvp175

Cited by 43 publications

(24 citation statements)

References 39 publications

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“…Such modifications are finally beginning to be identified. GSK3 has been reported to be cleaved to activated fragments by calpain (Goñi-Oliver et al, 2007; Goñi-Oliver et al, 2009) and by matrix metalloproteinase-2 (Kandasamy and Schulz, 2009), which may affect its selection of substrates to phosphorylate. A regulatory effect of acetylation on GSK3 activity was recently reported (Monteserin-Garcia et al, 2013).…”

Section: Regulation Of Gsk3-mediated Substrate Phosphorylationmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Beurel

Grieco

Jope

2015

Pharmacology & Therapeutics

1,396

1,178

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Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

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Section: Regulation Of Gsk3-mediated Substrate Phosphorylationmentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Beurel

Grieco

Jope

2015

Pharmacology & Therapeutics

1,396

1,178

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“…Activation of GSK-3β in hearts undergoing oxidative stress may be another downstream consequence of the intracellular actions of MMP-2. [35]…”

Section: Intracellular Targetsmentioning

confidence: 99%

Myocardial matrix metalloproteinase-2: inside out and upside down

DeCoux

Lindsey

Villarreal

et al. 2014

Journal of Molecular and Cellular Cardiology

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Since their inaugural discovery in the early 1960s, matrix metalloproteinases (MMPs) have been shown to mediate multiple physiological and pathological processes. In addition to their canonical function in extracellular matrix (ECM) remodeling, research in the last decade has highlighted new MMP functions, including proteolysis of novel substrates beyond ECM proteins, MMP localization to subcellular organelles, and proteolysis of susceptible intracellular proteins in those subcellular compartments. This review will provide a comparison of the extracellular and intracellular roles of MMPs, illustrating that MMPs are far more interesting than the one-dimensional view originally taken. We focus on the roles of MMP-2 in cardiac injury and repair, as this is one of the most studied MMPs in the cardiovascular field. We will highlight how understanding all dimensions, such as localization of activity and timing of interventions, will increase the translational potential of research findings. Building upon old ideas and turning them inside out and upside down will help us to better understand how to move the MMP field forward.

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“…This regulation involves the removal by calpain of a fragment from the N-terminal region of GSK-3, including the regulatory serines 9/21 (Goni-Oliver et al, 2007). Interestingly, GSK-3β has also been recently shown to be cleaved at the N-terminus (and subsequently activated) by matrix metallo-proteinase 2 (MMP-2) in cardiomyoblasts (Kandasamy and Schulz, 2009). …”

Section: Regulation By Proteolytic Cleavagementioning

confidence: 99%

Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies

Medina¹,

Garrido²,

Wandosell³

2011

Front. Mol. Neurosci.

104

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Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed and unusually active in resting, non-stimulated cells. In mammals, at least three proteins (α, β1, and β2), generated from two different genes, gsk-3α and gsk-3β, are widely expressed at both the RNA and protein levels although some tissues show preferential expression of some of the three proteins. Control of GSK-3 activity occurs by complex mechanisms that depend on specific signaling pathways, often controlling the inhibition of the kinase activity. GSK-3 appears to integrate different signaling pathways from a wide selection of cellular stimuli. The unique position of GSK-3 in modulating the function of a diverse series of proteins and its association with a wide variety of human disorders has attracted significant attention as a therapeutic target and as a means to understand the molecular basis of brain disorders. Different neurodegenerative diseases including frontotemporal dementia, progressive supranuclear palsy, and Alzheimer’s disease, present prominent tau pathology such as tau hyperphosphorylation and aggregation and are collectively referred to as tauopathies. GSK-3 has also been associated to different neuropsychiatric disorders, like schizophrenia and bipolar disorder. GSK-3β is the major kinase to phosphorylate tau both in vitro and in vivo and has been proposed as a target for therapeutic intervention. The first therapeutic strategy to modulate GSK-3 activity was the direct inhibition of its kinase activity. This review will focus on the signaling pathways involved in the control of GSK-3 activity and its pathological deregulation. We will highlight different alternatives of GSK-3 modulation including the direct pharmacological inhibition as compared to the modulation by upstream regulators.

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Glycogen synthase kinase-3 is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts

Cited by 43 publications

References 39 publications

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Myocardial matrix metalloproteinase-2: inside out and upside down

Modulation of GSK-3 as a Therapeutic Strategy on Tau Pathologies

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