Project: Research project

Project Details


This proposal entitled "Biochemical Mechanisms of Insulin Receptor
Endocytosis" focuses on the regulation of insulin receptor endocytosis.
The elucidation of insulin action at the cellular level is a significant
component of attempts to understand Type II diabetes. Insulin receptor
internalization is deficient in some insulin-resistance states and may play
an important role in the physiology of insulin action; furthermore, the
internalization of insulin-insulin receptor complexes in the liver is one
of the major physiological mechanisms for the clearance of serum insulin.
this proposal will identify structural motifs in the insulin receptor which
allow it to enter the endocytic system, and will identify the intracellular
proteins which mediate this recognition. The insulin receptor contains two
tyrosine residues in the cytoplasmic juxtamembrane region which are present
in the sequences GPDY953 and NPEY960; structural analysis both tyrosine
residues are in beta-turns; mutagenesis studies suggest that these
tyrosyl/beta-turns serve as recognition motifs for insulin receptor
internalization. This hypothesis will be tested by constructing mutant
receptors in which this tyrosine/beta-turn motif is specifically maintained
or disrupted. to further define regions of the receptor involved in
endocytosis, domain-specific anti-receptor antibodies and receptor-derived
peptides will be microinjected into intact cells. Finally, experiments
will be conducted to identify the proteins which regulate insulin receptor
endocytosis, using affinity chromatography techniques based on our
knowledge of endocytosis-specific receptor domains. These studies will
substantially add to our understanding of the mechanisms which govern the
endocytosis of the insulin receptor as well as other cell surface
Effective start/end date9/1/9212/31/92


  • Biochemistry


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