Gene interactions and pathways from curated databases and text-mining
J Pharmacol Sci 2013, PMID: 23698110

Inhibition of the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 by AICAR.

Shibata, Tomohito; Takaguri, Akira; Ichihara, Kazuo; Satoh, Kumi

AMP-activated protein kinase (AMPK) contributes to the acceleration of insulin signaling. However, the mechanism by which AMPK regulates insulin signaling remains unclear. Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling. Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-α in 3T3L1 adipocytes. We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside (AICAR) significantly inhibited the TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal-regulated kinase (ERK) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation. In addition, AICAR stimulation resulted in enhanced interaction between ERK and MAP kinase phosphatase-4 (DUSP9/MKP-4) without affecting DUSP9/MPK4 mRNA synthesis. Moreover, intraperitoneal administration (0.25 g/kg) of AICAR to db/db mice improved blood glucose levels and inhibited the phosphorylation of ERK in adipose tissue. In conclusion, we propose a new mechanism in which AICAR suppresses TNF-α-induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4. Taken together, these findings provide evidence that AMPK plays a crucial role in improving of type 2 diabetes.

Diseases/Pathways annotated by Medline MESH: Diabetes Mellitus, Type 2, Insulin Resistance
Document information provided by NCBI PubMed

Text Mining Data

IRS-1 → TNF-a: " Inhibition of the TNF-a Induced Serine Phosphorylation of IRS-1 at 636/639 by AICAR "

insulin → AMPK: " However, the mechanism by which AMPK regulates insulin signaling remains unclear "

insulin → insulin receptor substrate (IRS)-1: " Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling "

insulin → (IRS)-1: " Serine phosphorylation of insulin receptor substrate (IRS)-1 negatively regulates insulin signaling "

IRS-1 ⊣ AMPK: " Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-a in 3T3L1 adipocytes "

IRS-1 → tumor necrosis factor (TNF)-a: " Here we investigated the role of AMPK in serine phosphorylation of IRS-1 at 636/639 and 307, which is induced by tumor necrosis factor (TNF)-a in 3T3L1 adipocytes "

IRS-1 ⊣ AMPK: " We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside ( AICAR ) significantly inhibited the TNF-a induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal regulated kinase ( ERK ) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation "

IRS-1 → TNF-a: " We demonstrated that the AMPK activator 5-aminoimidazole-4-carboxamide-1-d-ribofuranoside ( AICAR ) significantly inhibited the TNF-a induced serine phosphorylation of IRS-1 at 636/639 and 307 by suppression of extracellular signal regulated kinase ( ERK ) phosphorylation but not c-Jun-NH2-terminal kinase (JNK) phosphorylation "

IRS-1 → TNF-a: " In conclusion, we propose a new mechanism in which AICAR suppresses TNF-a induced serine phosphorylation of IRS-1 at 636/639 and 307 by enhancing the interaction between ERK and DUSP9/MKP-4 "

Manually curated Databases

No curated data.