Gene interactions and pathways from curated databases and text-mining
Mol Cell Biol 1997, PMID: 9372969

Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes.

Sharma, P M; Egawa, K; Gustafson, T A; Martin, J L; Olefsky, J M

Activated insulin receptor (IR) interacts with its substrates, IRS-1, IRS-2, and Shc via the NPXY motif centered at Y960. This interaction is important for IRS-1 phosphorylation. Studies using the yeast two-hybrid system and sequence identity analysis between IRS-1 and IRS-2 have identified two putative elements, the PTB and SAIN domains, between amino acids 108 and 516 of IRS-1 that are sufficient for receptor interaction. However, their precise function in mediating insulin's bioeffects is not understood. We expressed the PTB and SAIN domains of IRS-1 in HIRcB fibroblasts and 3T3-L1 adipocytes utilizing replication-defective adenoviral infection to investigate their role in insulin signalling. In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin-induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1-associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen-activated protein kinase (MAPK) phosphorylation. However, epidermal growth factor-induced Shc and MAPK phosphorylation was unaffected by the overexpressed proteins. These findings were associated with a complete inhibition of insulin-stimulated cell cycle progression. In 3T3-L1 adipocytes, PTB or SAIN expression extinguished IRS-1 phosphorylation with a corresponding 90% decrease in IRS-1-associated PI 3-K activity. p70s6k is a downstream target of PI 3-K, and insulin-stimulated p70s6k was inhibited by PTB or SAIN expression. Interestingly, overexpression of either PTB or SAIN protein did not affect insulin-induced AKT activation or insulin-stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin. Thus, interference with the IRS-1-IR interaction inhibits insulin-stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression. In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin-stimulated AKT activation or glucose transport. These results indicate a bifurcation or subcompartmentalization of the insulin signalling pathway whereby some targets of PI 3-K (i.e., p70s6k) are dependent on IRS-1-associated PI 3-K and other targets (i.e., AKT and glucose transport) are not. IR-IRS-1 interaction is not essential for insulin's effect on glucose transport, and alternate, or redundant, pathways exist in these cells.

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Text Mining Data

Shc → insulin: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

Shc → PTB: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p44 → insulin: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p44 → PTB: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p42 → insulin: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p42 → PTB: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p70s6k → mitogen activated protein kinase: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation , and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p70s6k → insulin: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p70s6k → IRS-1: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation , and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

p70s6k → PTB: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

IRS-1 → insulin: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

IRS-1 → PTB: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

phosphatidylinositol 3-kinase (PI 3-K) → insulin: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

phosphatidylinositol 3-kinase (PI 3-K) → PTB: " In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1 associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen activated protein kinase ( MAPK ) phosphorylation "

Shc → epidermal growth factor: " However, epidermal growth factor induced Shc and MAPK phosphorylation was unaffected by the overexpressed proteins "

MAPK → epidermal growth factor: " However, epidermal growth factor induced Shc and MAPK phosphorylation was unaffected by the overexpressed proteins "

p70s6k ⊣ PTB: " p70s6k is a downstream target of PI 3-K, and insulin stimulated p70s6k was inhibited by PTB or SAIN expression "

p70s6k → insulin: " p70s6k is a downstream target of PI 3-K, and insulin stimulated p70s6k was inhibited by PTB or SAIN expression "

AKT → insulin: " Interestingly, overexpression of either PTB or SAIN protein did not affect insulin induced AKT activation or insulin stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin "

AKT — PTB: " Interestingly, overexpression of either PTB or SAIN protein did not affect insulin induced AKT activation or insulin stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin "

Shc → insulin: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

Shc → IRS-1-IR: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

MAPK → insulin: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

MAPK → IRS-1-IR: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

p70s6k → insulin: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

p70s6k → IRS-1-IR: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

IRS-1 → insulin: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

PI 3-K → insulin: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

PI 3-K → IRS-1-IR: " Thus, interference with the IRS-1-IR interaction inhibits insulin stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression "

AKT → insulin: " In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin stimulated AKT activation or glucose transport "

AKT → IR-IRS-1: " In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin stimulated AKT activation or glucose transport "

Manually curated Databases

No curated data.