The binding of various ligands, usually cytokines, such as interferons and interleukins, to cell-surface receptors, causes the receptors to dimerize, which brings the receptor-associated JAKs into close proximity.[5] The JAKs then phosphorylate each other on tyrosine residues located in regions called activation loops, through a process called transphosphorylation, which increases the activity of their kinase domains.[5] The activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins possessing SH2 domains.[5] STATs then bind to the phosphorylated tyrosines on the receptor using their SH2 domains, and then they are tyrosine-phosphorylated by JAKs, causing the STATs to dissociate from the receptor.[2] These activated STATs form hetero- or homodimers, where the SH2 domain of each STAT binds the phosphorylated tyrosine of the opposite STAT, and the dimer then translocates to the cell nucleus to induce transcription of target genes.[2] STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases - but since most receptors lack built-in kinase activity, JAKs are usually required for signalling.[3]