Mutual autophosphorylation

The JAK enzymes that are bound to the cytoplasmic domains of cytokine receptors are brought into close physical proximity following dimerization of the receptors. This allows JAKs bound to one receptor to catalyze phosphorylation of tyrosine residues of JAKs bound to the other in a process called mutual autophosphorylation. The effect is conversion of the JAKs into a high-activity form. They then phosphorylate tyrosine residues on the cytoplasmic domains of the receptors. 

Fig. 7.14). The enzyme is now activated and can perform an autophosphorylation in the autoinhibitory sequence. The phosphorylation takes place at a conserved Thr residue (Thr286 of the a subtype) and is intermolecular, i. e., neighboring subunits of the holoenzyme mutually phosphorylate one another. 

Enhancement of the catalytic activity is achieved by autophosphorylation in the activation segment within the kinase domain. It is generally assumed that this autophosphorylation takes place by a trans mechanism. Accordingly, two neighboring Tyr kinase domains in the receptor oligomer perform a mutual phosphorylation (see Fig. 8.3). 

Many extracellular stimuli are perceived by a cell through the receptor tyrosine kinases. Their cytoplasmic domains have kinase activity and phosphorylation motifs, which, after receptor activation, create sites for multiple components of the intracellular signalling network. Receptor activation is achieved by mutual intermolecular autophosphorylation of receptor subunits. This association is induced or stabilized in the receptor by ligand binding. 

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