Skip to main content
. Author manuscript; available in PMC: 2016 Sep 1.
Published in final edited form as: Cytokine. 2015 Jul 14;75(1):38–50. doi: 10.1016/j.cyto.2015.05.023

Figure 3. Regulation of signaling in response to IL-4 and IL-13.

Figure 3

Engagement of the type I IL-4 receptor by IL-4 brings about tyrosine phosphorylation of the associated JAKs, key tyrosine residues (pY1-5) in the cytoplasmic domain in IL-4Ra, STAT6 and IRS-2. STAT6 is dephosphorylated by SHP1, a protein tyrosine phosphatase (A). De-phosphorylation of STAT6 is critical to limit autoimmune and Th2 allergic inflammation, mast cell, B cell and epithelial cell activation. IRS-2 binds the regulatory p85 subunit of PI3-K, activating the enzyme to generate PIP3. In turn, PIP3 activates PDK1 and mTORC2. The proteins comprising the two mTOR complexes 1 and 2 are shown (B). TORC2 kinase phosphorylates AKT on serine 473 and to SGK1 in CD4+ T cells, leading to Th2 polarization. AKT inactivation of the Tsc1/2 complex prevents hydrolysis of GTP bound to Rheb. GTP-bound Rheb activates mTORC1, triggering a negative feedback loop via multiple pathways on IL-4-activated IRS-2/PI3-K/AKT signaling (C). The composition of the mTORC1 complex is shown. The mTORC1 complex also regulates macrophage polarization, as Raptor-deficient macrophages have enhanced M1 and M2 responses. The mTORC1 and mTORC2 complexes also regulate by unknown mechanisms, the polarization of T cells [adapted from (170)]. An additional negative regulatory pathway triggered by IL-4 is the induction of the SOCS proteins. SOCS1 binds IRS-2 and targets it for ubiquitin-mediated degradation (D). Phosphotyrosine, pY; phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3-K; phosphatidylinositol (3,4,5)-trisphosphate, PIP3; 3-phosphoinositide dependent protein kinase-1, PDK1; mTOR complex 2, mTORC2; serum and glucocorticoid-inducible kinase 1, SGK1; Ras homolog enriched in brain, RHEB; tuberous sclerosis complex 1, TSC1; regulatory-associated protein of mTOR, Raptor; mammalian lethal with Sec13 protein 8, mLST8; proline-rich Akt substrate of 40 kDa, PRAS40; DEP-domain-containing mTOR-interacting protein, DEPTOR; rapamycin-insensitive companion of TOR, RICTOR; mammalian stress-activated protein kinase-interacting protein 1, mSIN1; protein observed with RICTOR, PROTOR; suppressor of cytokine signaling 1, SOCS1.