Insulin receptor signal transduction tyrosine kinase

As work with vanadium compounds and diabetes in cell system has continued, it has become clear that there are also insulin-independent mechanisms at work. One insulin-independent signal transduction pathway appears to be involved in glycogen metabolism reactions in rat adipocytes [137] that also involve PI-3K. A major difference was that only vanadate promoted glycogenesis through the activation of a cytosolic protein tyrosine kinase, which was mediated in an insulin receptor-independent manner. 

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 contrast to the receptors for insulin and growth factors (see p. 388), the cytokine receptors (with a few exceptions) have no tyrosine kinase activity. After binding of cytokine (1), they associate with one another to form homodimers, join together with other signal transduction proteins (STPs) to form dimers, or promote dimerization of other... 

The insulin receptor substrate IRS couples the insulin receptor to sequential effector molecules (review Ogawa et al., 1998). On binding of insulin to the insulin receptor, the tyrosine kinase activity of the receptor is stimulated. The IRS protein is phosphory-lated at several Tyr residues, which then serve as attachment points for sequential effector molecules as e.g. the Grb2-mSos complex, the P13-kinase and the protein tyrosine phosphatase SHP-2. The IRS protein also has a phosphotyrosine binding domain and a PH domain. Both modules are required for signal transduction in vivo. It is assumed that the PTB domain binds to autophosphorylation sites of the insulin receptor and that the PH domain is involved in membrane association of IRS. 

Vanadate stimulates protein kinases in the cytosol, as demonstrated in adipose cells and extracts. The activation of a membrane and cytosolic protein tyrosine kinase have been demonstrated in adipocytes, and the membranous enzyme has been postulated to be a way to involve PI-3K actions without activation of insulin receptor substrate-1 (IRS-1) in the insulin signal transduction pathway [140], It is always difficult to determine if protein kinase activation is direct or the result of stimulation of a protein phosphatase. The fact that kinase stimulation was seen in isolated extracts after cell disintegration in this adipocyte cell system supports the idea that vanadium addition to cells could directly stimulate kinases via an as-yet-undetermined mechanism. In other experiments with 3T3-L1 adipocytes bis(acetylacetonato)oxovana-dium (IV) BMOV and bis(l-N-oxide-pyridine-2thiolato)oxovanadium (TV) caused increased tyrosine phosphorylation of both the insulin receptor and IRS-1 in a synergistic way with insulin, as measured by antibodies to phosphotyrosine residues [141]. 

Because the primary eveuts between insulin binding to its receptor and glucose transport are signal transduction events, a role for chromodulin in these events has been probed. Chromoduhn activates the tyrosine kinase activity of insulin-activated insulin receptor and activates a membrane phosphotyrosine phosphatase in adipocyte membranes. The addition of bovine liver chromodulin to rat adipocytic membranes in the presence of insuhn results in a concentration-dependent eightfold stimulation of insulin-dependent protein tyrosine kinase activity (while no activation... 

It has been known for a long time that a number of enzymes are regulated by insulin through phosphorylation and dephosphorylation at serine residues (Kahn, 1985). Therefore, a signal transduction from the tyrosine-specific insulin receptor kinase to a serine-specific kinase must occur. The serine kinase that might fulfil both functions in the insulin signal-transduction chain has not yet been identified however, there are several possible candidates for these so called switch kinases (Fig. 10). 

We now examine a signal-transduction pathway that reveals another clear example of how many signal-transduction pathways are poised to respond. This pathway is activated by the signal molecule epidermal rowth factor. Like that of the insulin receptor, the initiator of this pathway is a receptor tyrosine kinase. Both the extracellular and the intracellular domains of this receptor are ready for action, held in check only by... 

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