33 Harnessing developmental cues for cardiomyocyte production 2 Figure 1. There is interplay between Wnt, Hippo and insulin signaling during cardiomyocyte proliferation. Activation of the Hippo, canonical Wnt or IGF1/PI3K/AKT signaling pathways causes YAP/TAZ and β-catenin to enter the nucleus and cluster with their DNA-binding partners TEAD and TCF/LEF, which activates transcription of target genes and induces cell cycle activation. Conversely, when Dsh is inactivated due to lack of Wnt proteins, activated GSK-3β can phosphorylate β-catenin or YAP/TAZ, ultimately resulting in their degradation by the proteasome. Hippo signaling induced by, for example, N-cadherin junction-mediated cell-cell contact leads to the degradation of the YAP/TAZ complex through the MST1/2-SAV1-LATS1/2-MOB1-YAP/TAZ cascade. IGF1/PI3K/ AKT signaling can facilitate the entry of β-catenin into the nucleus via AKT kinase, which phosphorylates GSK-3β to inhibit its activation. AKT, RACα serine/threonine-protein kinase; APC, adenomatous polyposis coli protein; CK1α, casein kinase 1α; Dsh, disheveled; GSK-3β, glycogen synthase kinase-3; IGF1, insulin-like growth factor 1; IGF1R, IGF1 receptor; LATS1/2, large tumor suppressor homologue 1/2; LRP5/6, low-densitylipoprotein-related protein 5/6; MOB1, MOB kinase activator 1; MST1/2, mammalian STE20-like protein kinase 1/2; PI3 K, phosphoinositide 3-kinase; SAV1, protein Salvador homologue 1; TAZ, transcriptional coactivator with PDZ-binding motif; TCF/LEF, T-cell factor/lymphoid enhancer-binding factor; TEAD, TEA domain transcription factor family members; YAP, yes-associated protein; +p, phosphorylation; +u, ubiquitination. After CS16 and E12.5, cardiomyocyte proliferation rates decline further to maintain normal heart and embryo size ratios until birth. Postnatal heart growth is regulated via cellular hypertrophy (Günthel, Barnett, and Christoffels, 2018) (Figure 2 B,C). The insulin-like growth factor (IGF)/Akt pathway appears to promote physiological (and pathogenic) hypertrophy by activation of the ERK/MAPK and the phosphoinositide 3-kinase (PI3K)/Akt pathways in postnatal cardiomyocytes (DeBosch et al., 2006; Liu et al., 1996; Li et al., 2011).
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