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Fig. 1 | Nutrition & Metabolism

Fig. 1

From: Chronic over-nutrition and dysregulation of GSK3 in diseases

Fig. 1

Dual regulation of GSK3 by the PI3K/Akt/GSK3 pathway and PLIN2. Upon Wnt stimulation, the axin-GSK3-β-catenin complex (AGβC) is disassembled and the process is dependent of PLIN2 (denoted by curvy blue arrows) [1]. The released β-catenin from the AGβC complex activates transcription of factors involved in cell growth/survival (e.g. c-Myc, c/EBPα, and cyclin D1) or in insulin signaling (e.g. IRS1) [2], whereas the released GSK3 from the AGβC complex can be present in cytosol or recycle back to the AGβC complex [3]. The GSK3 activity is regulated mainly through the PI3K/Akt pathway that relays extracellular and intracellular (not shown) signals; − and + denote normal inhibitory and stimulatory signals, respectively, whereas −− and ++ (in red) denote over-inhibitory (e.g. the potency of the LY compounds used in (Ref 216)) and over-stimulatory (e.g. the potency of VEGF used in (Ref 5)) signals, respectively [4]. Different stages of kinase insensitivity and uncontrolled GSK3 activation are summarized in Table 1. Under − and −− conditions, the respective pSGSK3 levels are reduced but GSK3/pYGSK3 levels are increased (denoted by red blockage between the two) [5], perhaps inducing moderate and high activities of GSK3, respectively. Under ++ conditions, all the kinases tend to become insensitive (denoted by red blockages), generating unbridled GSK3 activity (Table 1) that can phosphorylate its substrates and render their degradation [6]. Accumulation of cytosolic lipid droplets (CLD) alters the association of PLIN2 and its binding proteins such as Dishevelled (Dvl), β-catenin, c/EBPα, and IRS1 [7]. The bold blue lines denote high affinity between PLIN2 and CLD [8]. LRP5/6: lipoprotein receptor-related proteins 5/6; Fz, frizzled; Gα, guanine nucleotide binding protein α subunit

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