ABSTRACT
As was amply demonstrated in the preceding chapters, insulin initiates its biological activity by activation of the protein tyrosine kinase, intrinsic to the β subunit of its receptor. The use of inhibitors of this enzymatic activity has thus represented a logical approach to elucidation of molecular details of insulin signal transduction. Success of this approach (as it would be for the use of inhibitors of any other activity) clearly depends on several assumptions including:
a. activation of the insulin receptor tyrosine kinase is the only way by which insulin initiates its signaling
b. inhibition of the receptor tyrosine kinase activity by the inhibitor is complete c. inhibition of this kinase activity is specific (i.e. at the concentrations used serine and/or
threonine protein kinase activities are unaffected) d. tyrosine kinase inhibition is specific to the insulin receptor (i.e. the tyrosine kinases of
other growth factor receptors are unaffected at the concentrations used)
While the first assumption is generally accepted, evidence exists that insulin is able to initiate at least some effects without necessarily activating the receptor tyrosine kinase (Gottschalk, 1991; Debant et al., 1988; Sung et al., 1989). Investigators have speculated that there are redundant mechanisms intrinsic to the insulin receptor that might be able to initiate the cascade of enzymatic activities involved in the early steps of insulin actions. Alternatively, if the sole role of the activation of the receptor tyrosine kinase is bringing the two β subunits into proximity, thus allowing their specific interaction, then any manner effecting such conformational change (such as use of anti-insulin receptor antibodies) could mimic the proximal steps of insulin signal transduction.
