Insulin signal transduction cascades

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...

At the cellular and molecular level, the binding of insulin to a specific membrane spanning receptor initiates a signal transduction cascade which ultimately produces the biological actions of the hormone. The insulin receptor is a tetrameric protein comprised of two a subunits that bind to insulin and two j3 subunits that are linked by disulfide bonds (55,56), and belongs to a subfamily of receptor typrosine kinases which also includes the insulin-like growth factor I (IGF-I) receptor. The a subunits are extracellularly located, while (S subunits span the membrane and have... 

Insulin Signaling Phosphorylation Cascades Are Central to Many Signal-Transduction Processes... 

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. 

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. 

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... 

Protein kinases are central to many signal-transduction pathways. Protein kinases are central to all three signal-transduction pathways described in this chapter. In the epinephrine-initiated pathway, cAMP-dependent protein kinase (PKA) lies at the end of the pathway, transducing information represented by an increase in cAMP concentration into covalent modifications that alter the activity of key metabolic enzymes. In the insulin- and EGF-initiated pathways, the receptors themselves are protein kinases and several additional protein kinases participate downstream in the pathways. Signal amplification due to protein kinase cascades are common features of each of these pathways and many others. Furthermore, protein kinases often phosphorylate multiple substrates, including many not considered herein, and by this means are able to generate a diversity of responses. 

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. 

---