Receptor tyrosine kinase Oligomerization

Besides cytoplasmic protein kinases, membrane receptors can exert protein kinase activity. These so-called receptor tyrosine kinases (RTK) contain a ligandbinding extracellular domain, a transmembrane motif, and an intracellular catalytic domain with specificity for tyrosine residues. Upon ligand binding and subsequent receptor oligomerization, the tyrosine residues of the intracellular domain become phosphory-lated by the intrinsic tyrosine kinase activity of the receptor [3, 4]. The phosphotyrosine residues ftmction as docking sites for other proteins that will transmit the signal received by the RTK. 

The insulin receptor is the prototype of a t3rrosine kinase receptor with a constimtive, oligomeric structure (Chapter 1). The receptor has been cloned and characterized in detail, notably by Axel Ullrich, R. C. Kahn and colleagues, see Chapter 1.29 Binding of insulin stimulates the intrinsic receptor tyrosine kinase. A crystal structure of the tyrosine kinase domain of the insulin receptor was solved. This leads to phosphorylation of tyrosine residues and to the recruitment and subsequent phosphorylation of substrates. 

Multivalent antigens lead to the dimerization or oligomerization of transmembrane immunoglobulins, an essential step in their activation. This mode of activation is reminiscent of that of receptor tyrosine kinases. 

Gadella, T. W. J. and Jovin, T. M. (1995). Oligomerization of epidermal growth-factor receptors on A431 cells studied by time-resolved fluorescence imaging microscopy—a stereochemical model for tyrosine kinase receptor activation. J. Cell Biol. 129, 1543-58. 

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. 

The insulin receptor is the prototype of a tyrosine kinase receptor with a constitutive oligomeric structure. The signalling form is a a.2/ 2 tetramer, but the unit structure is a heterodimer, consisting of a- and P-subunits. But, in contrast to the homo-and heterodimers of other RTK growth factor receptors, the formation of the insulin receptor oligomer is constitutive and not dependent on ligand binding (see Fig. 1.5). 

As a consequence of ligand binding to cytokine receptors, activation of a tyrosine kinase activity, which is not part of the receptor protein, is observed. In most cases this tyrosine kinase is permanently associated with one of the subunits ofthe receptor, and ligand-induced restructuring or hetero-oligomerization ofthe receptor induces activation of this tyrosine kinase. The tyrosine kinases most frequently associated with cytokine receptor subunits belong to the family of Janus kinases. However, protein tyrosine kinases ofthe Src family like Lck, Fyn and Tyk have also been shown to be direct downstream components of the cytokine receptors (see Section 11.2.2). 

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