1996 Fiscal Year Final Research Report Summary
The mechanism of degradation of mutant insulin receptors.
| Project/Area Number |
07457221
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
内分泌・代謝学
|
|---|
| Research Institution | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
|---|
Principal Investigator |
KOBAYASHI Masashi Toyama Medical & Pharmaceut. University, Department of Medicine, Professor, 医学部, 教授 (80115758)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TAKATA Yasumitsu Toyama Medical & Pharmaceut. University Department of Medicine, Assistant Prof, 医学部, 助手 (50242491)
|
|---|
| Project Period (FY) |
1995 – 1996
|
| Keywords | Malecular chaperones / Insulin receptor Disease / Insulin Resistance |
|---|
| Research Abstract |
We indentified two novel heterozygous missense mutations of the insulin receptor gene : the Asp 1179 mutation in one family and the Leu 1193 mutation in two unrelated families with extreme insulin resistance. In these patients, the number of insulin receptors on the cell surfacc was found to be markedly decreased by insulin binding and surface labeling studies in transformedlymphocytes. Insulin binding to the transfected COS 7 cells and Rat-1 cells with both mutant cDNAs was also decreased to 5-31% of normal, and the mutant insulin receptors showed a markedly decreased tyrosine kinase activity. Although biosynthetic labeling studies revealed the both mutant receptors were synthesized as 190-kDa proreceptors, the degradation rate of the mutant proreccptors ws 2-fold faster than that of the wild type proreceptors. Interestingly, two molecular chaperones, Hsc 70 and Hsp 90 bound with high affinity to these abnormal insulin receptor precursors in cells and intracellular beta-subunit GST-fusion proteins with these mutations. Furthermore, microinjection of anti-Hsp 90 antibody prevented the degradation of these mutant insulin proreceptors and recruited them to the cell surface. These results suggest that Asp 1179 an Leu 1193 mutations in the insulin receptor kinase domain are unique in causing decreased insulin receptor number on the cell surface and that molecular chaperons play an important role for the accelerated intracellular degradation of these mutant insulin receptors.
|
