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Functional Analysis of Signal Complexes Containing Insulin Receptor Substrates (IRSs)

keywords_en.jpgInsulin, IGF, Metabolic Syndrome, Diabetes, Cancer 

division_en.jpg Basic Life Sciences Laboratory of Biomedical Chemistry

position_en.jpg Assistant Professor

Outline

Background

Insulin and insulin-like growth factors (IGFs) play important roles in the regulation of carbohydrate/lipid metabolism and somatic growth. Their binding to the specific receptors activates receptorintrinsic tyrosine kinases, followed by tyrosine phosphorylation of
the substrates including IRSs. Stimulation of target cells with
various hormones, cytokines and nutritional factors often
suppresses tyrosine phosphorylation of IRSs, which causes
insulin resistance and subsequent metabolic syndrome. In
contrast, aberrantly intense tyrosine phosphorylation of IRSs
often promote cancer malignancy. However, molecular
mechanisms under the regulation of tyrosine phosphorylation of
IRSs remain unclear.

Research Summary

We had found that IRSs form high-molecular-mass complexes containing various proteins, and that the complexes can modulate insluin/IGFs signals and bioactivities. Thus, we identified components of the complexes and analyzed their functions.

Result

We identified E3 ubiquitin ligase Nedd4 as one of IRS-associated proteins. Mono-ubiquitination of IRSs by Nedd4 causes the recruitment of IRSs to plasma membrane, which leads increases in their availability to receptor tyrosine kinases and the augmentation of insulin/IGFs signals. These findings raised the possibility that changes of the
interaction of Nedd4 with IRSs or Nedd4 activity might be related to pathology of insulin resistance and cancer
malignancy. Analyses of other IRSs-associated proteins are in progression.

For Application

We expect to collaborate to screening chemical compounds targeting to IRSs-associate proteins with pharmaceutical companies. If we can manipulate their molecular functions using compounds, it will enable fine-tuning of insulin/IGFs activities.
This study will contribute to the development of a novel therapeutic approach toward metabolic syndrome and cancer.

Competitive Advances

Although thiazolidine derivatives and biguanides are widely used as insulin sensitizer, their mechanisms of action remain unclear. We propose IRSs-associate proteins as novel candidates of molecular targets in metabolic syndrome and cancer therapeutics. Drugs targeting of IRSs-associated proteins can modulate insulin/IGF activities with high specificity, and this specific mechanisms of action will offer advantages over other existing drugs.

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Mol Cell Endocrinol. 2011 Sep 15; 344 (1-2): 81-9, Biochem Biophys Res Commun. 2011 Jan 21; 404 (3): 767-73,
The best presentation award in Gordon Research Conference: Insulin like growth factors in physiology and disease, Ventura, CA, 2011.2.

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