Signal transduction kinase cascades

A case in point is the structure determination of the insulin receptor substrate-1 (IRS-1). Insulin binds to a membrane-bound receptor that is a ligand-activated protein tyrosine kinase. Upon insulin binding there is an autophosphorylation of several tyrosine residues on the cytosolic side of the receptor. This enhances the tyrosine kinase activity of the insulin receptor towards other substrates and is required for signal transduction. A cascade of events is initiated, the first of which is the phosphorylation of IRS-1. This occurs when IRS-1 binds to the insulin receptor via a specific domain of the protein that is termed the phosphotyrosine binding (PTB) domain. 

Ludwig S (2007) Influenza viruses and MAP kinase cascades - novel targets for antiviral intervention, Signal Transduction 7 81-88... 

This linear scheme of signal transduction (Fig. 12) from hypothetical membrane receptors to [Ca " ] and IP3 increases, calcium-calmodulin interaction, kinases activation and gene transcription is clearly an oversimplification of the reality several receptors must exist that are connected to different transduction cascades that activate a series of defense genes. Cross-talking between the pathways further complicates the picture. However, this represents a starting model on which to elaborate more refined hypotheses. 

Each of these pathways involves a kinase cascade resulting in the phosphorylation and activation of the MAP kinase family member. Each contains a dual phosphorylation site (TEY, TPY, or TGY) and the central residue in the motif characteristic of the class, as shown in Table 8.1. It is evident that cells are endowed with parallel signal-transduction pathways and that they may operate individually or in combination to initiate specific patterns of gene expression. Additionally, crosstalk between the pathways undoubtedly occurs. None of these pathways has a unique function it is more likely that the combination of pathways that are activated (or silenced) together with the... 

Components of Tyrosine Kinase Signal Transduction Cascades Are Discovered as Cellular (or Viral) Oncogenes... 

Berhow, M.T., Hiroi, N., Nestler, EJ. Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J. Neurosci. 16 4707, 1996. 

Pierce, R.C., Pierce-Bancroft, A.F., Prasad, B.M. Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade. J. Neurosci. 19 8685, 1999. 

The diverse effects of insulin (see p. 160) are mediated by protein kinases that mutually activate each other in the form of enzyme cascades. At the end of this chain there are kinases that influence gene transcription in the nucleus by phosphorylating target proteins, or promote the uptake of glucose and its conversion into glycogen. The signal transduction pathways involved have not yet been fully explained. They are presented here in a simplified form. 

The classical example is blood clotting, where successive steps involving enzyme-catalyzed proteolysis converts an inactive (or weakly active) proenzyme into its highly active form. Although unknown at the time of Wald s classical report, kinase-type and nucleotidyltransferase-type reactions (See Enzyme Cascade Kinetics) are frequently the source of biological signal transduction and amplification. 

Fig. 4. VEGF binds to the Ig-like binding domain ligand of I lk-1, activating the intracellular tyrosine kinase domain and instigating a signal transduction cascade that leads to angiogenesis.

---