Binding of IL-10 to its receptor causes phosphorylation and activation of the receptor-associated Janus tyrosine kinases, JAK1 and TYK2 (Finbloom & Winestock 1995), leading to phosphorylation of two conserved tyrosine residues (Y446 and Y496) within the intracellular domain of IL10RA, which serve as redundant docking sites for STAT3 (Ho et al. 1995, Weber-Nordt et al. 1996).
The details of JAK kinase activation are unclear. The classical model suggests that receptor dimerization, induced by ligand binding, brings the two JAK family kinases into proximity, so that they are able to trans-activate (phosphorylate) each other (Donnelly et al. 1999, Waters et al. 2015) but it is also possible that ligand binding causes a conformational change in a pre-existing receptor dimer that withdraws trans pseudo-kinase inhibition for paired kinases, which then autophosphorylate (Waters et al. 2014, Waters & Brooks 2015). JAK1, like all JAK kinases, has two adjacent tyrosines in its activation loop (Y1034, Y1035). It is not known which of these becomes phosphorylated in response to IL10 binding, or if phosphorylation at one site rather than the other has functional consequences. In vitro, phosphorylation at Y1034 has a greater enhancing effect on JAK1 catalytic ability (Wang et al. 2003) and is the more commonly observed phosphorylation site (see PhosphoSitePlus). Similarly TYK2 has two adjacent tyrosines, the first (Y1054) is the more commonly observed (see PhosphoSitePlus).