FIGURE 3

FIGURE 3

Schematic of the Wnt and PI3K/Akt/mTOR signaling pathways. (A) The inactive state of the Wnt signaling pathway. In the absence of Wnt ligands, the destruction complex (Axin, adenomatous polyposis coli (APC), casein kinase 1 (CK1), and GSK3β) phosphorylates β-catenin, marking it for ubiquitination (Ub) by beta-transducin repeat-containing protein (β-TrCP). β-catenin is degraded by proteasomes, thus preventing transcription of Wnt target genes. (B) The activation of the Wnt signaling pathway occurs upon the binding of Wnt ligands to Frizzled receptors. Next, CK1 and GSK3β phosphorylate the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor, activating DVL, which inhibits the destruction complex and prevents the degradation of β-catenin. Stabilized β-catenin accumulates in the cytoplasm and translocates to the nucleus as a transcriptional co-activator with T-cell factor/lymphoid enhancer factor (TCF/LEF) to induce transcription of Wnt target genes. (C) The PI3K/Akt/mTOR signaling pathway. Growth factors bind to a receptor tyrosine kinase (RTK), causing dimerization and autophosphorylation of the receptors. PI3K is recruited to the membrane and catalyzes the production of phosphatidylinositol-3, 4, 5-triphosphate (PIP₃) from phosphatidylinositol-4, 5-bisphosphate (PIP₂) which is negatively regulated by phosphatase and tensin homolog (PTEN). PIP₃ activates Akt, a serine/threonine kinase that regulates numerous cell survival and cell cycle processes, including the inhibition of GSK3β and TSC1/2. The inhibition of TSC1/2 releases Rheb to activate mTOR complex 1 (mTORC1), comprised of mTOR and the regulatory associated protein of mTOR (Raptor). The upregulation of mTORC1 activates several important cellular processes including protein synthesis, proliferation, cell growth, and autophagy. During times of cellular metabolic stress, LKB1, a serine-threonine kinase, activates AMP-activated protein kinase (AMPK) which activates TSC2 and inhibits Raptor to downregulate mTORC1 signaling. This figure was constructed using information from several reviews (Shaw, 2009; Kaidanovich-Beilin and Woodgett, 2011; Porta et al., 2014; Martin-Orozco et al., 2019; Prossomariti et al., 2020).