Insulin Receptor Substrate (IRS)-1 and IRS-2 Are Tyrosine-phosphorylated and Associated with Phosphatidylinositol 3-Kinase in Response to Brain-derived Neurotrophic Factor in Cultured Cerebral Cortical Neurons

Abstract

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, promotes differentiation and survival of various types of neurons in the central nervous system. BDNF binds to and activates the tyrosine kinase receptor, TrkB, initiating intracellular signaling and exerting its effects. Phosphatidylinositol 3-kinase (PI3-K), which has been implicated in promotion of neuronal survival by neurotrophic factors, is a component in the signaling pathway of BDNF. We examined how BDNF activates PI3-K in cultured cerebral cortical neurons. We found that insulin receptor substrate (IRS)-1 and -2 are involved in the BDNF signaling pathway that activates PI3-K. IRS-1 and -2 were tyrosine-phosphorylated and bound to PI3-K in response to BDNF. This BDNFstimulated signaling via IRS-1 and -2 was inhibited by K-252a, an inhibitor of Trk tyrosine kinase. In addition, signaling via IRS-1 and -2 was markedly sustained as well as the BDNF-induced tyrosine phosphorylation of TrkB. On the other hand, we observed no association of PI3-K with TrkB in response to BDNF. These results indicate that the activation of TrkB by BDNF induces the activation of PI3-K via IRS-1 and -2 rather than by a direct interaction of TrkB with PI3-K in cultured cortical neurons.

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

“…Interestingly, IRS2 signals have been reported to mediate the action of BDNF (Yamada et al 1997) and hippocampal IRS2 is critical for LTP induction upon tetanic stimulation (Martín et al 2012). Because PI3K activity is necessary for CAF LTP (Fig.…”

“…Adaptor proteins such as GRB‐associated binder‐1, IRS1 and IRS2 are recruited to activate Trk receptors and their phosphorylation leads to downstream activation of PI3K/Akt signaling (Holgado‐Madruga et al 1997; Yamada et al 1997; White 2006). In the present work, we show that caffeine rapidly induces the tyrosine phosphorylation of IRS2, but not IRS1, and that treatment of hippocampal slices with ryanodine blocks caffeine‐induced IRS2 phosphorylation, indicating that release of Ca 2+ from intracellular ryanodine‐sensitive stores is necessary for the activation of PI3K/Akt signaling in postsynaptic neurons.…”

Neuroprotection by Brain-derived Neurotrophic Factor Is Mediated by Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase

“…Camptothecin-BDNF can activate several signal transduction systems including the PI 3-kinase and the ERK pathways (16,54). Stimulation of PI 3-kinase can lead to the activation and phosphorylation of protein kinase Akt (25).…”

Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system

“…Second, IRS (insulin receptor substrates IRS-1 and IRS-2) and Gab-1 (Grb-associated binder-1) are adapter proteins that mediate the association and activation of PI3K (Holgado-Madruga et al 1997;Yamada et al 1997), as PI3K does not directly interact with the Trk receptors. PI3K is especially implicated in neuronal survival via the activation of PKB/AKT kinase (Franke et al 1997;Crowder and Freeman 1998), resulting in phosphorylation and inactivation of the proapoptotic protein BAD of the Bcl-2 family (Datta et al 1997).…”