Gene interactions and pathways from curated databases and text-mining
Endocrinology 2007, PMID: 17158207

Ceramide-activated protein phosphatase involvement in insulin resistance via Akt, serine/arginine-rich protein 40, and ribonucleic acid splicing in L6 skeletal muscle cells.

Ghosh, Nilanjan; Patel, Niketa; Jiang, Kun; Watson, James E; Cheng, Jin; Chalfant, Charles E; Cooper, Denise R

Elevated TNFalpha levels are associated with insulin resistance, but the molecular mechanisms linking cytokine signaling to impaired insulin function remain elusive. We previously demonstrated a role for Akt in insulin regulation of protein kinase CbetaII alternative splicing through phosphorylation of serine/arginine-rich protein 40, a required mechanism for insulin-stimulated glucose uptake. We hypothesized that TNFalpha attenuated insulin signaling by dephosphorylating Akt and its targets via ceramide-activated protein phosphatase. Western blot analysis of L6 cell lysates demonstrated impaired insulin-stimulated phosphorylation of Akt, serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog. TNFalpha increased serine/threonine phosphatase activity of protein phosphatase 1 (PP1) in response to C6, but not insulin, suggesting a ceramide-specific effect. Myriocin, an inhibitor of de novo ceramide synthesis, blocked stimulation of the PP1 activity. Ceramide species measurement by liquid chromatography-mass spectrometry showed consistent increases in C24:1 and C16 ceramides. Effects of TNFalpha and C6 on insulin-stimulated phosphorylation of glycogen synthase kinase 3beta were prevented by myriocin and tautomycin, a PP1 inhibitor, further implicating a de novo ceramide-PP1 pathway. Alternative splicing assays demonstrated that TNFalpha abolished insulin-mediated inclusion of the protein kinase CbetaII exon. Collectively, our work demonstrates a role for PP1-like ceramide-activated protein phosphatase in mediating TNFalpha effects blocking insulin phosphorylation cascades involved in glycogen metabolism and alternative splicing.

Diseases/Pathways annotated by Medline MESH: Insulin Resistance
Document information provided by NCBI PubMed

Text Mining Data

insulin ⊣ TNFalpha: " We hypothesized that TNFalpha attenuated insulin signaling by dephosphorylating Akt and its targets via ceramide activated protein phosphatase "

serine/arginine-rich protein → TNFalpha: " Western blot analysis of L6 cell lysates demonstrated impaired insulin stimulated phosphorylation of Akt, serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog "

serine/arginine-rich protein → insulin: " Western blot analysis of L6 cell lysates demonstrated impaired insulin stimulated phosphorylation of Akt, serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog "

Akt → TNFalpha: " Western blot analysis of L6 cell lysates demonstrated impaired insulin stimulated phosphorylation of Akt , serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog "

Akt → insulin: " Western blot analysis of L6 cell lysates demonstrated impaired insulin stimulated phosphorylation of Akt , serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog "

glycogen synthase kinase 3beta → TNFalpha: " Western blot analysis of L6 cell lysates demonstrated impaired insulin stimulated phosphorylation of Akt, serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog "

glycogen synthase kinase 3beta → insulin: " Western blot analysis of L6 cell lysates demonstrated impaired insulin stimulated phosphorylation of Akt, serine/arginine-rich protein 40, and glycogen synthase kinase 3beta in response to TNFalpha and the short chain C6 ceramide analog "

TNFalpha → insulin: " TNFalpha increased serine/threonine phosphatase activity of protein phosphatase 1 (PP1) in response to C6, but not insulin , suggesting a ceramide-specific effect "

phosphatase 1 (PP1) → TNFalpha: " TNFalpha increased serine/threonine phosphatase activity of protein phosphatase 1 (PP1) in response to C6, but not insulin, suggesting a ceramide-specific effect "

phosphatase 1 (PP1) → insulin: " TNFalpha increased serine/threonine phosphatase activity of protein phosphatase 1 (PP1) in response to C6, but not insulin , suggesting a ceramide-specific effect "

glycogen synthase kinase 3beta → insulin: " Effects of TNFalpha and C6 on insulin stimulated phosphorylation of glycogen synthase kinase 3beta were prevented by myriocin and tautomycin, a PP1 inhibitor, further implicating a de novo ceramide-PP1 pathway "

glycogen synthase kinase 3beta — TNFalpha: " Effects of TNFalpha and C6 on insulin stimulated phosphorylation of glycogen synthase kinase 3beta were prevented by myriocin and tautomycin, a PP1 inhibitor, further implicating a de novo ceramide-PP1 pathway "

Manually curated Databases

No curated data.