Protein tyrosine kinases binding domains

Tyro protein tyrosine kinase-binding protein, DNAX-activation protein 12, DAP12, KARAP Upstream activation site Ubiquitinlike modifiers Universal conditions direct sequencing Ubiquitin-domain proteins uridine diphosphate Uridine-5 -diphospho-iV-acetylglucosamine Uracil DNA glycosylase Upstream open reading frame... 

A phosphotyrosine residue in the carboxyl terminus of Src and related protein tyrosine kinases binds to its own SH2 domain to generate the inhibited from of Src (Section 15.5). Removal of the phosphate from this residue will activate the kinase. 

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

Cytokine receptors can be divided into two groups those whose intracellular domains exhibit intrinsic protein tyrosine kinase (PTK) activity and those whose intracellular domains are devoid of such activity. Many of the latter group of receptors, however, activate intracellular soluble PTKs upon ligand binding. 

Typically of receptor tyrosine kinases, binding of insulin to the extracellular domains of the IR causes autophosphorylation of specific tyrosine residues within the intracellular region of the [3 units. Some RTKs, as described above and as illustrated by JAKs described above and also shown in Figure 4.20, would at this point recruit adaptor proteins to bind directly to the phosphorylated intracellular... 

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 ... 

Fig. 8.13. SH3 domains and specificity of tyrosine kinases. Binding of the SH3 domain of the substrate protein SI to the Pro-rich sequence of the tyrosine kinase increases affinity of the tyrosine kinase for its substrate and favors its phosphorylation. Proteins (S2) that possess Tyr phosphorylation sites but do not have SH3 domains are not converted by the tyrosine kinase, or only to a much lower extent.

The integrins do not have any enzyme activity in their own cytoplasmic domain, but on hgand binding, stimulation of tyrosine phosphorylation is observed on the cytoplasmic side of many cells, such as fibroblasts and platelets. The exact configuration of protein-protein interactions on the cytosolic side of the integrins is not clear and the mechanism of stimulation of protein tyrosine kinases is unknown. Some components of the focal adhesion points, such as the structural protein tensin, have SH2 and SH3 domains that may serve as specific attachment points for tyrosine kinases and other signal proteins. 

Fig. 16.11. Model of the association of Fyn kinase with the NMDA receptor The NMDA receptor is shown as a tetramer of NRl and NR2 subunits. The C-terminal tail of NR2 interacts with PDZ2 of PSD-95. The protein tyrosine kinase Fyn is assumed to bind to PDZ3 of PSD-95 via its SH2 domain. Fyn also is anchored to the ceU membrane via its myristoylated N-terminus. GK guanylate kinase domain of PSD-95. According to Sala and Sheng (1999), with permission.

The bacterial chemoreceptor (Figs. 11-8 and 19-5) has a very small ligand-binding domain and a larger internal domain that activates a histidine kinase. Many growth-factor receptors, including the insulin receptor (Figs. 11-11,11-12), have internal domains with protein tyrosine kinase activity. 

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