Activation of Cytoplasmic Tyrosine Kinases

As a consequence of hgand binding to cytokine receptors, activation of a tyrosine kinase activity, which is not part of the receptor protein, is observed. The coupling between cytokine receptor and tyrosine kinase can occur by two means  

Ligand binding induces the association of the cytoplasmic tyrosine kinase with the receptor. The extracellular signal leads the tyrosine kinase to make contact with the activated receptor in this case. 

Hie tyrosine kinase may also be permanently associated with the receptor in a non-covalent manner and is activated on ligand binding to the receptor. 

In both cases, it is assumed that ligand binding leads to restructuring of the intracellular region of the oligomeric receptor, so that binding surfaces are created for productive association of the tyrosine kinase. 

Examples of receptor-associated tyrosine kinases are given in Table 8.1. Most of the associated protein tyrosine kinases belong to the family of Src kinases (see 8.3) and the Jak kinases (see 11.1.3). 

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In some cases, binding of hormone to a surface receptor induces a tyrosine kinase cascade, even though the receptor is not itself a tyrosine kinase. The growth hormone receptor is one example of such a system — the interaction of growth hormone with its receptor leads to activation of cytoplasmic tyrosine kinases, with results conceptually similar to that seen with receptor kinases. 

Signal transduction via the receptor-like CD 45 protein tyrosine phosphatase in cells of the blood forming system requires its intracellularly localized phosphatase activity. The cytoplasmic tyrosine kinases p56 " and p59 are thought to be cellular substrates... 

The T and B cell antigen receptors do not have any intrinsic protein tyrosine kinase activity. Rather, antigen binding leads to recruitment and activation of protein tyrosine kinases on the cytoplasmic side of the receptor. Probably, coupling of the tyrosine kinase takes place via the ARAM motif directly. 

JAK is a family of cytoplasmic tyrosine kinases that are associated with cytokine receptors and play a major role in the initial steps of cytokine signaling. Upon ligand binding, JAKs are activated by /ra .s-phosphorylation of two receptor-bound JAK molecules and subsequently phosphorylate a number of substrates including the cytokine receptor (D3, S3, W8). The phosphorylated receptor... 

Src and Src related kinases are included in the large family of cytoplasmic tyrosine kinases on the basis of their common domain structure acety-lated amino terminus, SH2 and SH3 domains, and highly conserved catalytic domain (Williams et al., 1998). Src kinase has little activity in cells in the absence of an activating signal, but many stimuli increase Src enzymatic activity via phosphorylation mechanisms (Cooper and Howell,... 

These include the receptors for erythropoietin, somatotropin, and interferons. Their receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (Janus kinases [JAKs]). JAKs phosphory-late signal transducers and activators of transcription (STAT) molecules. STATs dimerize and then dissociate, cross the nuclear membrane, and modulate gene transcription. 

Their receptors are membrane spanning and on activation can activate a distinctive set of cytoplasmic tyrosine kinases (Janus kinases [JAKs]). 

Insulin binding activates the tyrosine kinase activity associated with the cytoplasmic domain of its receptor as shown in F jure 1-9-4. There is no trimeric G protein, enzyme, or second messenger required to activate this protein tyrosine kinase activity ... 

Three Trks have been identified, Trk A, B and C. Ligand-binding induces Trk receptor homodimerization. This activates the intrinsic cytoplasmic tyrosine kinase activity, resulting in receptor autophosphorylation and initiation of an intracellular response. A characteristic feature of the Trk family of receptors is the presence of a leucine-rich region near the N-terminal (extracellular) end of the molecule. 

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