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. Author manuscript; available in PMC: 2023 Aug 1.
Published in final edited form as: J Allergy Clin Immunol. 2022 Aug;150(2):266–276. doi: 10.1016/j.jaci.2022.06.012

Figure 1: Canonical and non-canonical IL-4 and IL-13 signaling pathways:

Figure 1:

Canonical pathways (marked in dashed green box) activated in response to type I and type II IL-4R signaling involve JAK/STAT-mediated phosphorylation of STAT6. Activation of the type 1 IL-4R also leads to activation of IRS-2 and downstream activation of PI3K, Akt and mTOR. Non-canonical activation (marked in red dashed box) of SRC, ERK1/2 and p38 MAPK in response to IL-4, or ERK1/2 and PI3K in response to IL-13, have also been described to contribute important biological outcomes. As activation of PI3K/AKT/mTOR is directly attributable to γc/JAK3-driven phosphorylation of Y647 in IL-4Rα in the type 1 IL-4R complex, but IL-13Rα1/TYK2-driven phosphorylation of Y647 has not been described for the type II IL-4R, PI3K/AKT activation is considered canonical downstream of the type I IL-4R, but non-canonical downstream of the type II IL-4R complex. IL-13 can also signal through IL-13Rα2 (marked in dashed blue box) to activate/phosphorylate Akt/PKC and Ras/ERK1/2 pathway to induce TGFβ, Tenascin-c and other IL-13Rα2-associated genes.