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.
Highlights
Glycogen synthase kinase-3 (GSK3) was originally identified as a regulator of glycogen synthesis but is known to influence many important cellular processes[1,2,3]
Alterations in GSK3 activity are found in age-related human diseases including diabetes, cancer, Alzheimer’s disease (AD), schizophrenia, Bipolar Disorder, inflammation, and cardiac hypertrophy[3,7,8,9]
In this paper we identify a novel GSK3 substrate, Rab-GTPase binding effector protein 2 (RABEP2), map the residues targeted by GSK3 in cells, and show priming is required for GSK3 to regulate RABEP2 in vivo
Summary
Glycogen synthase kinase-3 (GSK3) was originally identified as a regulator of glycogen synthesis but is known to influence many important cellular processes[1,2,3]. Different groups of GSK3 substrates have distinct ‘priming kinases’, and this regulatory mechanism provides opportunities for physiological, pathophysiological or pharmacological manipulation of specific substrates primed by a common protein kinase, independent of direct GSK3 regulation. It remains to be seen whether there are disease related priming defects that enhance specific subsets of GSK3 substrate phosphorylation. In this paper we identify a novel GSK3 substrate, RABEP2 (a proposed regulator of Rab signaling), map the residues targeted by GSK3 in cells, and show priming is required for GSK3 to regulate RABEP2 in vivo This is a relatively poorly studied protein with the potential to regulate key membrane associated biological processes. Screening of RABEP2 phosphorylation in GSK3-associated diseases should help establish whether the regulation of RABEP2 is altered in human diseases where GSK3 activity (or specific priming events) is increased
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