Tyrosine residues autophosphorylation

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

An early step in Fak activation is a high stoichiometry autophosphorylation of a tyrosine residue (Y397)... 

The current understanding on activation of Tec kinases fits into a two-step model. In the first step an intramolecular interaction between the SH3 domain and aproline-rich region in the TH domain is disrupted by binding ofthe PH domain to phosphoinositides, G protein subunits, or the FERM domain of Fak. These interactions lead to conformational changes of Tec and translocation to the cytoplasmic membrane where, in a second step, Src kinases phosphorylate a conserved tyrosine residue in the catalytic domain thereby increasing Tec kinase activity. Autophosphorylation of a tyrosine residue in the SH3 domain further prevents the inhibitory intramolecular interaction resulting in a robust Tec kinase activation. 

In principle, RTK autophosphorylation could occur in cis (within a receptor monomer) or in trans (between two receptors in a dimer). In the first case, ligand binding would cause a change in receptor conformation that would facilitate c/ s-autophosphorylation of tyrosine residues located within or outside the PTK domain. In the second case, no conformational change must occur upon dimerization. The simple proximity effect would provide sufficient opportunity for trans-phosphorylation of tyrosines in the cytoplasmic domain by a second RTK. 

Figure 11.2 Structure of the insulin receptor (a). Binding of insulin promotes autophosphorylation of the (3-subunits, where each (3-subunit phosphorylates the other (3-subunit. Phosphate groups are attached to three specific tyrosine residues (tyrosines 1158, 1162 and 1163), as indicated in (b). Activation of the (3-subunit s tyrosine kinase activity in turn results in the phosphorylation of various intracellular (protein) substrates which trigger the mitogen-activated protein kinase and/or the phosphoinositide (PI-3) kinase pathway responsible for inducing insulin s mitogenic and metabolic effects. The underlying molecular events occurring in these pathways are complex (e.g. refer to Combettes-Souverain, M. and Issad, T. 1998. Molecular basis of insulin action. Diabetes and Metabolism, 24, 477-489)...

RPTK activation. The activity of RPTKs is normally suppressed in their quiescent state. This suppression is due to the numerous loose and unstructured conformations of the activation loop (A loop) within the catalytic domain the majority of these conformations interfere with substrate and ATP binding. However, a subset of these conformations is amenable to binding of substrate and ATP, resulting in activation of the RPTKs. Phosphorylation of the tyrosine residue(s) in the A loop shifts the equilibrium towards the active conformation. Because of steric hindrance, PTK catalytic domains appear to be unable to autophosphorylate tyrosine residue(s) in the A loop within the same molecule rather frans-autophosphoryla-tion between two different catalytic domains is necessary for their activation. As a consequence, ligand-induced dimerization is an important step in the activation of RPTKs (Fig. 24-7). 

The receptor autophosphorylates tyrosine residues on the internal portion (p subunit), turning the receptor into active kinase. 

It is not clear whether V(V) or V(IV) (or both) is the active insulin-mimetic redox state of vanadium. In the body, endogenous reducing agents such as glutathione and ascorbic acid may inhibit the oxidation of V(IV). The mechanism of action of insulin mimetics is unclear. Insulin receptors are membrane-spanning tyrosine-specific protein kinases activated by insulin on the extracellular side to catalyze intracellular protein tyrosine phosphorylation. Vanadates can act as phosphate analogs, and there is evidence for potent inhibition of phosphotyrosine phosphatases (526). Peroxovanadate complexes, for example, can induce autophosphorylation at tyrosine residues and inhibit the insulin-receptor-associated phosphotyrosine phosphatase, and these in turn activate insulin-receptor kinase. 

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... 

Once autophosphorylation begins, a complex of other events ensues. An insulin receptor substrate (IRS-1) binds the receptor and is phosphorylated on tyrosine residues, allowing proteins with SH2 (src homology) domains to bind to the. phosphotyrosine residues on IRS-1 and become active. In this way, the receptor activates several enzyme cascades, which involve ... 

Fig. 8.6. Functions of autophosphorylation of receptor tyrosine kinases. Autophosphorylation of receptor tyrosine kinases takes place in trans, i.e., between neighboring protomers of the receptor. The catalytic domain of the receptor is shown as a shaded segment. As a consequence of autophosphorylation, the intrinsic tyrosine kinase activity of the receptor is stimulated. Effector proteins can also bind to the activated receptor. Binding takes place with specific phosphotyrosine binding domains (SH2 or PTB domains) at phosphotyrosine residues of the activated receptor. A critical factor for further signal transduction is the membrane association of the effector proteins that enter into binding with the activated receptor. Details of the effector proteins can be found as follows phospholipase Cy 5.6.2 Src kinase 8.3.2 pl20 GAP 9.4 Grb2, She, IRS 8.5 PI3-kinase 6.6.1 Syp tyrosine phosphatase 8.4.

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