Figure 4.

Left panel: Canonical IGF-I and IGF-II signaling through the IGF-IR. IGF-I and IGF-II bind the IGF-IR at the extracellular α subunit, leading to autophosphorylation of β subunit residues, which then act as docking sites for insulin receptor substrates (IRS) 1–4 and other signaling proteins, such Shc. IRS-1 recruits the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), which through the catalytic effects of its p110 subunit recruits protein kinase B (Akt) to the cell membrane, where it is phosphorylated and activated. Activated Akt has many substrates, including Bcl2 antagonist of cell death (Bad), glycogen synthase kinase 3β (GSK3β), forkhead transcription factors (such as FoxO1), and Akt substrate of 160 kDa (AS160). These factors are chiefly involved in regulating apoptosis and cell metabolism. Akt also regulates protein synthesis by phosphorylating tuberous sclerosis protein (TSC2), releasing its inhibition of Rheb to activate the mammalian target of rapamycin (mTORC1). The phosphorylation of IRS-1 and Shc can also lead to recruitment of growth factor receptor-bound protein 2 (Grb2), Son of Sevenless (SOS), and Ras, with subsequent activation via a phosphorylation series of the mitogen-activated protein kinase (MAPKKK, MAPKK, and MAPK) pathways, leading to cell proliferation, migration, and survival. Right panel: More novel signaling through the IGF-IR and IR mediated via additional interactions of the C-terminal intracellular region of the activated receptors with factors such as discoidin domain receptors (DDRs), focal adhesion kinase (FAK), receptor tyrosine-protein kinases such as Src, mesenchymal epithelial transition factor (MET), and recepteur d'origine nantais (RON). The activated receptor can also interact with Janus kinase (JAK), signal transducer, and activator of transcription (STAT). These interactions contribute to receptor actions on autophagy, epithelial–mesenchymal transition (EMT), stemness, and anoikis.