Tyrosine phosphorylation signal transduction cascades

Our consideration of the signal-transduction cascades initiated by epinephrine and insulin included examples of how components of signal-transduction pathways are poised for action, ready to be activated by minor modifications. For example, G-protein a subunits require only the binding of GTP in exchange for GDP to transmit a signal. This exchange reaction is thermodynamically favorable, but it is quite slow in the absence of an appropriate activated 7TM receptor. Similarly, the tyrosine kinase domains of the dimeric insulin receptor are ready for phosphorylation and activation but require the presence of insulin bound between two a subunits to draw the activation loop of one tyrosine kinase into the active site of a partner tyrosine kinase to initiate this process. 

In attempts to further understand the signal transduction cascades that regulate capacitation, our laboratory has recently correlated mouse, human, and bovine sperm capacitation with an increase in protein tyrosine phosphorylation of a variety of substrates (Visconti et ah, 1995a Carrera et ah, 1996 Galantino-Homer et ah, 1997). Many of these results have since been corroborated by other labs (Aitken et ah, 1995 Leclerc et ah, 1996 Luconi et ah, 1996 Emiliozzi and Fenichel, 1997). Using the mouse as an experimental paradigm, our laboratory has demonstrated... 

Figure 1 Insulin signal transduction cascade (simplified). Intracellular kinases affected by tyrosine phosphorylation activation/deactivation under phosphotyrosine phosphatase (PTPase) regulation (vanadium-inhibitable) include (especially) IRS-I, IRS-2, she, and MAPK. V indicates possible sites of vanadium s mechanism of action. Cytosolic protein tyrosine kinase (CytPTK, not shown) stimulation by phosphatase inhibition is independent of the insulin cascade, but is also multi-step, and is particularly susceptible to vanadyl stimulation...

Genistein has been used for years as a model inhibitor of protein tyrosine kinases (PTKs). This ubiquitous enzyme, which is also present in thyroid foUicular ceUs, is involved in phosphorylation of tyrosyl residues of membrane-bound receptors leading to signal transduction. One of the signal transduction cascades leads to topoisomerase II, which participates in DNA replication. Blocking PTK activity is one of the mechanisms believed to be responsible for the anticancer potential of genistein. For reviews addressing this issue, which are beyond the scope of this chapter, see Peterson (1995), and Ravindranath et al (2004). 

Signal transduction The binding of insulin to the a-subunits of the insulin receptor induces conformational changes that are transduced to the 3-subunits. This promotes a rapid autophosphorylation of a specific tyrosine residue on each 3-subunit (see Figure 23.7). Autophosphorylation initiates a cascade of cellsignaling responses, including phosphorylation of a family of pro teins called insulin receptor substrate (IRS) proteins. At least four... 

The control of cellular proliferation and differentiation in response to external stimuli is achieved by signal transduction pathways, which are regulated in part by the co-ordinated action of protein kinases and phosphatases. In eukaryotic cells the protein kinases involved fall primarily into two classes, those that phosphorylate tyrosine residues and those that are specific for serine and threonine residues. Prokaryotic cells also rely on protein phosphorylation cascades for regulation of cellular activities, but the kinases involved are primarily histidine kinases, which are part of the sensing domain of two-component regulatory systems. These histidine kinases and their associated response regulators are involved in a range of adaptive responses by bacteria. 

---