title: PTEN, a widely known negative regulator of insulin/PI3K signaling, positively regulates neuronal insulin resistance.
abstract: Lipid and protein tyrosine phosphatase, phosphatase and tension homologue (PTEN), is a widely known negative regulator of insulin/phosphoinositide 3-kinase signaling. Down-regulation of PTEN is thus widely documented to ameliorate insulin resistance in peripheral tissues such as skeletal muscle and adipose. However, not much is known about its exact role in neuronal insulin signaling and insulin resistance. Moreover, alterations of PTEN in neuronal systems have led to discovery of several unexpected outcomes, including in the neurodegenerative disorder Alzheimer's disease (AD), which is increasingly being recognized as a brain-specific form of diabetes. In addition, contrary to expectations, its neuron-specific deletion in mice resulted in development of diet-sensitive obesity. The present study shows that PTEN, paradoxically, positively regulates neuronal insulin signaling and glucose uptake. Its down-regulation exacerbates neuronal insulin resistance. The positive role of PTEN in neuronal insulin signaling is likely due to its protein phosphatase actions, which prevents the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), the kinases critically involved in neuronal energy impairment and neurodegeneration. Results suggest that PTEN acting through FAK, the direct protein substrate of PTEN, prevents ERK activation. Our findings provide an explanation for unexpected outcomes reported earlier with PTEN alterations in neuronal systems and also suggest a novel molecular pathway linking neuronal insulin resistance and AD, the two pathophysiological states demonstrated to be closely linked.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Punjab, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Gupta
authors.forename: Chinmoy Sankar
authors.initials: CS
authors.lastname: Dey
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000072181:Inositol Polyphosphate 5-Phosphatases; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020935:MAP Kinase Signaling System; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference
chemical_list: D016564:Amyloid beta-Protein Precursor; D002070:Butadienes; D007328:Insulin; D009570:Nitriles; D010716:Phosphatidylinositols; C113580:U 0126; C118303:phosphoinositide-3,4,5-triphosphate; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse