Fig. 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-density-lipoprotein-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.