Regulation of protein phosphorylation by insulin/IGF-1 Yang,Yu-Ying Tseng, Yu-Hua C.Ronald Kahn.

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Regulation of protein phosphorylation by insulin/IGF-1 Yang,Yu-Ying Tseng, Yu-Hua C.Ronald Kahn

Insulin an anabolic hormone with strong metabolic effects. If concentration of glucose is too high, then insulin will be released to metabolize the glucose. When it binds to its receptor, the receptor will autophosphorylation, activate a family of IRS proteins, and lead the transmitting the signal downstream.

IGF-1 insulin-like growth factor 1,has it ’ s own receptor.It has a similar signal transduction pathways to insulin ’ s. IGF-I mediates many actions of growth hormone, and it stimulates cell replication, cell differentiation and the synthesis of cellular products. As for their biological effects, in general, IGF-1 is mainly responsible for mitogenic effects

Insulin/IGF-1 pathway

IRS (insulin receptor substrate) proteins IRS-1 its deficiency causes growth retardation and insulin resistance, which will lead to type 2 diabetes. IRS-2 insulin resistance, lead to serious diabetes when it absents

IRS-3 no glucose metabolism or growth problems when it is absent IRS-4 slight defects in growth, reproduction, and glucose homoeostasis

Method brown pre-adipocytes from different IRS KO mice Western blotting -- sample preparation cell + for scrap cell normalize cell -- loading gel -- transfer -- immunoblotting -- ECL

WtIRS-1 KO IRS-3 KO m2 IRS-1,3 KO IRS-2 KO IRS-3 KO m1 ST5 (min) CREB-p ATF-p WtIRS-1 KO + IRS-1 IRS-1 KO + IRS-2 IRS-1 KO + IRS-4 IRS-1 KO + IRS CREB-p ATF-p ST6 (min) Creb-p Insulin (100 nm)

WtIRS-1 KO IRS-3 KO m1 IRS-1,3 KO IRS-2 KO IRS-3 KO m2 ST5 (min) CREB-p ATF-p Creb-p (IGF-1 100nm) WtIRS-1 KO ST6 (min) IRS-1 KO + IRS IRS-1 KO + IRS-2 IRS-1 KO + IRS-3 IRS-1 KO + IRS-4 CREB-p ATF-p

Akt-Juk (min) IGF-1 (100 nm) ST WtIRS-1 KOIRS-2 KOIRS-1,3 KOP85a KO + P85a IRS-1 KO + IRS-1 IRS-3 KO Akt Jnk (min) Insulin (100 nm) ST WtIRS-1 KOIRS-2 KOIRS-1,3 KOP85a KO + P85a IRS-1 KO + IRS-1 IRS-3 KO Akt Jnk

Result Insulin and IGF-1 almost have the same stimulative efficiency. Compare with Wt cell, the KO cells did have lower efficiency in signaling. IRS1+3KO cells didn’t lower much efficiency in signaling. Akt-Juk shows stronger bands than Creb-p in the same time period stimulating.

Conclusion both insulin and IGF-1 can cross-react with each other's receptor when used at high dosages. Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and protein accumulation (10 to 40%) compared to wild- type cells (90 to 100%).

IRS-1KO gene maybe complementary to IRS-2, IRS-3 gene, but not IRS-4 gene. IRS-1KO and IRS-3 KO cell didn ’ t result in much deficiency in signaling, maybe there ’ s other pathways for the insulin/IGF-1 signaling.