Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3)

Lisa Logie, Lidy Van Aalten, Axel Knebel, Thomas Force, C. James Hastie, Hilary MacLauchlan, David G. Campbell, Robert Gourlay, Alan Prescott, Jane Davidson, Will Fuller, Calum Sutherland (Lead / Corresponding author)

Research output: Contribution to journalArticle

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102 Downloads (Pure)

Abstract

Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue. Rab-GTPase binding effector protein 2 (RABEP2) was identified as a novel GSK3 substrate and GSK3 phosphorylation of RABEP2 at Ser200 was enhanced by prior phosphorylation at Ser204, fitting the known consensus sequence for GSK3 substrates. Both residues are phosphorylated in cells while only Ser200 phosphorylation is reduced following inhibition of GSK3. RABEP2 function was originally identified as a Rab5 binding protein. We did not observe co-localisation of RABEP2 and Rab5 in cells, while ectopic expression of RABEP2 had no effect on endosomal recycling. The work presented identifies RABEP2 as a novel primed substrate of GSK3, and thus a potential biomarker for GSK3 activity, but understanding how phosphorylation regulates RABEP2 function requires more information on physiological roles of RABEP2.
Original languageEnglish
Article number17682
Pages (from-to)1-14
Number of pages14
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 15 Dec 2017

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rab GTP-Binding Proteins
Glycogen Synthase Kinase 3
Carrier Proteins
Phosphorylation
rab5 GTP-Binding Proteins
Physiological Phenomena
Consensus Sequence

Keywords

  • GSK3
  • Diabetes
  • Heart disease
  • Alzheimer's disease

Cite this

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title = "Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3)",
abstract = "Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue. Rab-GTPase binding effector protein 2 (RABEP2) was identified as a novel GSK3 substrate and GSK3 phosphorylation of RABEP2 at Ser200 was enhanced by prior phosphorylation at Ser204, fitting the known consensus sequence for GSK3 substrates. Both residues are phosphorylated in cells while only Ser200 phosphorylation is reduced following inhibition of GSK3. RABEP2 function was originally identified as a Rab5 binding protein. We did not observe co-localisation of RABEP2 and Rab5 in cells, while ectopic expression of RABEP2 had no effect on endosomal recycling. The work presented identifies RABEP2 as a novel primed substrate of GSK3, and thus a potential biomarker for GSK3 activity, but understanding how phosphorylation regulates RABEP2 function requires more information on physiological roles of RABEP2.",
keywords = "GSK3, Diabetes, Heart disease, Alzheimer's disease",
author = "Lisa Logie and {Van Aalten}, Lidy and Axel Knebel and Thomas Force and Hastie, {C. James} and Hilary MacLauchlan and Campbell, {David G.} and Robert Gourlay and Alan Prescott and Jane Davidson and Will Fuller and Calum Sutherland",
note = "Funding: British Heart Foundation (PG/12/3/29344)",
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month = "12",
day = "15",
doi = "10.1038/s41598-017-17087-6",
language = "English",
volume = "7",
pages = "1--14",
journal = "Scientific Reports",
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publisher = "Nature Publishing Group",

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Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3). / Logie, Lisa; Van Aalten, Lidy; Knebel, Axel; Force, Thomas; Hastie, C. James; MacLauchlan, Hilary; Campbell, David G.; Gourlay, Robert; Prescott, Alan; Davidson, Jane; Fuller, Will; Sutherland, Calum (Lead / Corresponding author).

In: Scientific Reports, Vol. 7, 17682, 15.12.2017, p. 1-14.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3)

AU - Logie, Lisa

AU - Van Aalten, Lidy

AU - Knebel, Axel

AU - Force, Thomas

AU - Hastie, C. James

AU - MacLauchlan, Hilary

AU - Campbell, David G.

AU - Gourlay, Robert

AU - Prescott, Alan

AU - Davidson, Jane

AU - Fuller, Will

AU - Sutherland, Calum

N1 - Funding: British Heart Foundation (PG/12/3/29344)

PY - 2017/12/15

Y1 - 2017/12/15

N2 - Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue. Rab-GTPase binding effector protein 2 (RABEP2) was identified as a novel GSK3 substrate and GSK3 phosphorylation of RABEP2 at Ser200 was enhanced by prior phosphorylation at Ser204, fitting the known consensus sequence for GSK3 substrates. Both residues are phosphorylated in cells while only Ser200 phosphorylation is reduced following inhibition of GSK3. RABEP2 function was originally identified as a Rab5 binding protein. We did not observe co-localisation of RABEP2 and Rab5 in cells, while ectopic expression of RABEP2 had no effect on endosomal recycling. The work presented identifies RABEP2 as a novel primed substrate of GSK3, and thus a potential biomarker for GSK3 activity, but understanding how phosphorylation regulates RABEP2 function requires more information on physiological roles of RABEP2.

AB - Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue. Rab-GTPase binding effector protein 2 (RABEP2) was identified as a novel GSK3 substrate and GSK3 phosphorylation of RABEP2 at Ser200 was enhanced by prior phosphorylation at Ser204, fitting the known consensus sequence for GSK3 substrates. Both residues are phosphorylated in cells while only Ser200 phosphorylation is reduced following inhibition of GSK3. RABEP2 function was originally identified as a Rab5 binding protein. We did not observe co-localisation of RABEP2 and Rab5 in cells, while ectopic expression of RABEP2 had no effect on endosomal recycling. The work presented identifies RABEP2 as a novel primed substrate of GSK3, and thus a potential biomarker for GSK3 activity, but understanding how phosphorylation regulates RABEP2 function requires more information on physiological roles of RABEP2.

KW - GSK3

KW - Diabetes

KW - Heart disease

KW - Alzheimer's disease

U2 - 10.1038/s41598-017-17087-6

DO - 10.1038/s41598-017-17087-6

M3 - Article

C2 - 29247183

VL - 7

SP - 1

EP - 14

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 17682

ER -