Project: Research project

Project Details


Exposure of cells to insulin promotes phosphorylation of the insulin
receptor's cytoplasmic domain on serine, threonine and tyrosine. Insulin-
dependent tyrosine phosphorylation probably reflects receptor
autophosphorylation, and the receptor is known to be only a tyrosine
kinase. Thus, the serine and threonine phosphorylation observed most
likely reflects receptor-induced phosphorylation by an exogenous kinase(s). Serine phosphorylation of the insulin receptor has been correlated with
decreases, in the receptor's intrinsic tyrosine kinase and with decreases
in insulin's ability to stimulate cellular metabolism. Therefore, serine
phosphorylation of the insulin receptor may be an important regulator od
insulin action. We have discovered an affinity-purified insulin receptor preparation which
contains a copurifying serine/threonine kinase phosphorylates the insulin
receptor on several sites phosphorylated in the intact cell identification
of these serine and threonine phosphorylation sites makes possible
experiments to explore the role of these phosphorylated residues in
controlling receptor serine and threonine phosphorylation sites--via
expression of mutant receptors lacking specific serines and threonines--on
insulin signalling in the intact cell. The following questions will be addressed: 1. Does site-directed mutagenesis of serine and threonine phosphorylation
sites change the pattern and level of insulin receptor tyrosine kinase
autophosphorylation in intact cells? Comparison of phosphopeptide maps
from normal insulin receptors and insulin receptors mutated at serine or
threonine phosphorylation sites may reveal the point(s) in the receptor
autophosphorylation cascade disrupted by these phosphorylations. 2. What effect does the alteration of serine of threonine phosphorylation
sites by site-directed mutagenesis have on the rate of receptor
internalization and insulin-dependent receptor down-regulation? Recent
reports indicate that mutant insulin receptors lacking tyrosine kinase
activity are not phosphorylated on serine or threonine, nor can these
receptors undergo ligand-induced down-regulation. 3. Does the alteration of one or more sites of serine/threonine
phosphorylation by site-directed mutagenesis modify insulin signalling?
Serine phosphorylation of the insulin receptor correlates well with
decreased insulin activation of glycogen synthase and tyrosine
aminotransferase. If insulin receptor serine/threonine phosphorylation is
an important regulator of insulin action the loss of these phosphorylation
sites may enhance and prolong cellular responses to insulin. Detailed investigation of these questions will provide fundamental
information regarding the biochemical mechanisms that control insulin
signalling and may provide a useful model for exploring insulin resistance
at the cellular level.
Effective start/end date6/1/905/31/96


  • National Institutes of Health: $94,368.00
  • National Institutes of Health: $107,600.00
  • National Institutes of Health: $101,020.00


  • Medicine(all)


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