Interleukin-4 receptor subunit apha (IL4R), Interleukin-2 receptor subunit gamma (IL2RG) and Janus kinase 1 (JAK1), but not Non-receptor associated tyrosine kinase 2 (TYK2), JAK2 or JAK3 are tyrosine phosphorylated in response to IL4 (Bhattacharjee et al. 2013). The order of these phosphorylation events is not clear. Based on studies of other interleukin receptors and their associated JAKs it is likely that JAK1 autophosphorylates and then phosphorylates IL4R and IL2RG.
IL4R contains 5 conserved tyrosine residues, Y497, Y575, Y603, Y631, and Y713, which can all play a role in signaling through this receptor. Structure-function analyses have revealed that Y497 is part of the IL4R motif that is necessary for the recruitment of IRS1 and IRS2 to IL4R and is critical for IL4-dependent cell proliferation (Keegan et al. 1994). STAT6 signaling requires one of tyrosines Y575, Y603, and Y631 (Ryan et al. 1996). Y713 is part of an immunotyrosine-based inhibitory motif (ITIM) shown to be important in the negative regulation of IL4 and IL13 responses (Kashiwada et al. 2001).