Adaptor protein containing pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif (APPL1)-mediated adiponectin and insulin-signaling pathways

Model of adaptor protein containing pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif (APPL1)-mediated adiponectin and insulin-signaling pathways. Adiponectin (Ad) binding to the extracellular COOH terminus of adiponectin receptor 1 (AdipoR1) recruits APPL1 to the intracellular NH2 terminus of AdipoR1 and activation of AMPK, p38 MAPK, and Rab5. 1) Activation of the AMP-activated kinase (AMPK)/tuberous sclerosis complex (TSC)1/2 signaling pathway reduces mammalian target of rapamycin (mTOR)/p70 S6 (S6K)-mediated serine phosphorylation of insulin receptor substrate (IRS) proteins, which results in the enhancement of IRS tyrosine phosphorylation and insulin signaling to activate Akt, leading to glucose uptake. 2) Activated AMPK phosphorylates and thereby inactivates acetyl-CoA carboxylase (ACC), resulting in fatty acid oxidation. 3) Activated AMPK phosphorylates endothelial nitric oxide (NO) synthase (eNOS), leading to the formation of eNOS-heat shock protein 90 (Hsp90) complex and generation of NO to mediate the vasodilating effect of adiponectin. 4) Activated AMPK inhibits IKK-NF-κB-phosphatase and tensin homolog (PTEN) pathway, mediating the cytoprotective effect of adiponectin. 5) Binding of adiponectin to AdipoR1 stimulates glucose transporter 4 (GLUT4) translocation and glucose uptake through phosphorylated AMPK, phosphorylated p38 MAPK, and Rab5.

Publication

APPL1: role in adiponectin signaling and beyond. (2009) Sathyaseelan S. Deepa, et al. Am J Physiol Endocrinol Metab. 2009 Jan;296(1):E22-E36. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions