A partnership with the proteasome: the destructive nature of GSK3

Holly Robertson, John D. Hayes, Calum Sutherland (Lead / Corresponding author)

Research output: Contribution to journalArticle

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116 Downloads (Pure)

Abstract

Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates includes alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (b-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-b-TrCP ‘destruction hit-list’ that allows the co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-b-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.
Original languageEnglish
Pages (from-to)77-92
Number of pages16
JournalBiochemical Pharmacology
Volume147
Early online date1 Nov 2017
DOIs
Publication statusPublished - Jan 2018

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Glycogen Synthase Kinase 3
Proteasome Endopeptidase Complex
beta-Transducin Repeat-Containing Proteins
Phosphorylation
Proteins
Substrates
Protein Stability
Ubiquitination
Enzymes
Glycogen
Enzyme activity
Homeostasis
Phosphotransferases
Glucose
Stabilization

Keywords

  • Animals
  • Glycogen Synthase Kinase 3/metabolism
  • Humans
  • Proteasome Endopeptidase Complex/metabolism
  • Protein Binding/physiology
  • Signal Transduction/physiology
  • Ubiquitination/physiology

Cite this

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title = "A partnership with the proteasome: the destructive nature of GSK3",
abstract = "Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates includes alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (b-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-b-TrCP ‘destruction hit-list’ that allows the co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-b-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.",
keywords = "Animals, Glycogen Synthase Kinase 3/metabolism, Humans, Proteasome Endopeptidase Complex/metabolism, Protein Binding/physiology, Signal Transduction/physiology, Ubiquitination/physiology",
author = "Holly Robertson and Hayes, {John D.} and Calum Sutherland",
note = "The authors work on GSK3 has been supported by MRC award MR/N009851/1 (JH and CS), a BBSRC studentship (to HR) and the British Heart Foundation award number PG/12/3/29344 (to CS).",
year = "2018",
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pages = "77--92",
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A partnership with the proteasome : the destructive nature of GSK3. / Robertson, Holly; Hayes, John D.; Sutherland, Calum (Lead / Corresponding author).

In: Biochemical Pharmacology, Vol. 147, 01.2018, p. 77-92.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A partnership with the proteasome

T2 - the destructive nature of GSK3

AU - Robertson, Holly

AU - Hayes, John D.

AU - Sutherland, Calum

N1 - The authors work on GSK3 has been supported by MRC award MR/N009851/1 (JH and CS), a BBSRC studentship (to HR) and the British Heart Foundation award number PG/12/3/29344 (to CS).

PY - 2018/1

Y1 - 2018/1

N2 - Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates includes alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (b-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-b-TrCP ‘destruction hit-list’ that allows the co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-b-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.

AB - Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates includes alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (b-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-b-TrCP ‘destruction hit-list’ that allows the co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-b-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.

KW - Animals

KW - Glycogen Synthase Kinase 3/metabolism

KW - Humans

KW - Proteasome Endopeptidase Complex/metabolism

KW - Protein Binding/physiology

KW - Signal Transduction/physiology

KW - Ubiquitination/physiology

U2 - 10.1016/j.bcp.2017.10.016

DO - 10.1016/j.bcp.2017.10.016

M3 - Article

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VL - 147

SP - 77

EP - 92

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

ER -