Volume 272, Number 48, Issue of November 28, 1997 pp. 30334-30339
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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

(Received for publication, June 11, 1997, and in revised form, August 19, 1997)

Masashi Yamada , Hiroshi Ohnishi ^¶ , Shin-ichiro Sano ^¶ , Atsushi Nakatani , Toshihiko Ikeuchi and Hiroshi Hatanaka

From the  Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565, Japan and the ^¶ Mitsubishi Kasei Institute of Life Science, 11 Minamiooya, Machida, Tokyo 194, Japan

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 BDNF-stimulated 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Y. Yi, I. Shin, and C. L. Arteaga Type I Transforming Growth Factor {beta} Receptor Binds to and Activates Phosphatidylinositol 3-Kinase J. Biol. Chem., March 18, 2005; 280(11): 10870 - 10876. [Abstract] [Full Text] [PDF]

				A. M. Hinsby, J. V. Olsen, and M. Mann Tyrosine Phosphoproteomics of Fibroblast Growth Factor Signaling: A ROLE FOR INSULIN RECEPTOR SUBSTRATE-4 J. Biol. Chem., November 5, 2004; 279(45): 46438 - 46447. [Abstract] [Full Text] [PDF]

				M. Seki, T. Tanaka, H. Nawa, T. Usui, T. Fukuchi, K. Ikeda, H. Abe, and N. Takei Involvement of Brain-Derived Neurotrophic Factor in Early Retinal Neuropathy of Streptozotocin-Induced Diabetes in Rats: Therapeutic Potential of Brain-Derived Neurotrophic Factor for Dopaminergic Amacrine Cells Diabetes, September 1, 2004; 53(9): 2412 - 2419. [Abstract] [Full Text] [PDF]

				A. Motegi, J. Fujimoto, M. Kotani, H. Sakuraba, and T. Yamamoto ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth J. Cell Sci., July 1, 2004; 117(15): 3319 - 3329. [Abstract] [Full Text] [PDF]

				K. Ketterer, S. Rao, H. Friess, J. Weiss, M. W. Buchler, and M. Korc Reverse Transcription-PCR Analysis of Laser-Captured Cells Points to Potential Paracrine and Autocrine Actions of Neurotrophins in Pancreatic Cancer Clin. Cancer Res., November 1, 2003; 9(14): 5127 - 5136. [Abstract] [Full Text] [PDF]

				C. E. N. Reiter, L. Sandirasegarane, E. B. Wolpert, M. Klinger, I. A. Simpson, A. J. Barber, D. A. Antonetti, M. Kester, and T. W. Gardner Characterization of insulin signaling in rat retina in vivo and ex vivo Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E763 - E774. [Abstract] [Full Text] [PDF]

				M. Schubert, D. P. Brazil, D. J. Burks, J. A. Kushner, J. Ye, C. L. Flint, J. Farhang-Fallah, P. Dikkes, X. M. Warot, C. Rio, et al. Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation J. Neurosci., August 6, 2003; 23(18): 7084 - 7092. [Abstract] [Full Text] [PDF]

				J. Xu, J. E. Yeon, H. Chang, G. Tison, G. J. Chen, J. Wands, and S. de la Monte Ethanol Impairs Insulin-stimulated Neuronal Survival in the Developing Brain: ROLE OF PTEN PHOSPHATASE J. Biol. Chem., July 11, 2003; 278(29): 26929 - 26937. [Abstract] [Full Text] [PDF]

				T. Numakawa, D. Yokomaku, K. Kiyosue, N. Adachi, T. Matsumoto, Y. Numakawa, T. Taguchi, H. Hatanaka, and M. Yamada Basic Fibroblast Growth Factor Evokes a Rapid Glutamate Release through Activation of the MAPK Pathway in Cultured Cortical Neurons* J. Biol. Chem., August 2, 2002; 277(32): 28861 - 28869. [Abstract] [Full Text] [PDF]

				J. Egea, C. Espinet, R. M. Soler, X. Dolcet, V. J. Yuste, M. Encinas, M. Iglesias, N. Rocamora, and J. X. Comella Neuronal survival induced by neurotrophins requires calmodulin J. Cell Biol., August 6, 2001; 154(3): 585 - 598. [Abstract] [Full Text] [PDF]

				M. Bibel and Y.-A. Barde Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system Genes & Dev., December 1, 2000; 14(23): 2919 - 2937. [Full Text]

				M. Hetman, J. E. Cavanaugh, D. Kimelman, and Z. Xia Role of Glycogen Synthase Kinase-3beta in Neuronal Apoptosis Induced by Trophic Withdrawal J. Neurosci., April 1, 2000; 20(7): 2567 - 2574. [Abstract] [Full Text] [PDF]

				M.-A. Abbott, D. G. Wells, and J. R. Fallon The Insulin Receptor Tyrosine Kinase Substrate p58/53 and the Insulin Receptor Are Components of CNS Synapses J. Neurosci., September 1, 1999; 19(17): 7300 - 7308. [Abstract] [Full Text] [PDF]

				H. D. Venters, Q. Tang, Q. Liu, R. W. VanHoy, R. Dantzer, and K. W. Kelley A new mechanism of neurodegeneration: A proinflammatory cytokine inhibits receptor signaling by a survival peptide PNAS, August 17, 1999; 96(17): 9879 - 9884. [Abstract] [Full Text] [PDF]

				M. Hetman, K. Kanning, J. E. Cavanaugh, and Z. Xia Neuroprotection by Brain-derived Neurotrophic Factor Is Mediated by Extracellular Signal-regulated Kinase and Phosphatidylinositol 3-Kinase J. Biol. Chem., August 6, 1999; 274(32): 22569 - 22580. [Abstract] [Full Text] [PDF]

				S. V. Bhave, L. Ghoda, and P. L. Hoffman Brain-Derived Neurotrophic Factor Mediates the Anti-Apoptotic Effect of NMDA in Cerebellar Granule Neurons: Signal Transduction Cascades and Site of Ethanol Action J. Neurosci., May 1, 1999; 19(9): 3277 - 3286. [Abstract] [Full Text] [PDF]

				F. X. Zhang, R. Rubin, and T. A. Rooney N-Methyl-D-aspartate Inhibits Apoptosis through Activation of Phosphatidylinositol 3-Kinase in Cerebellar Granule Neurons. A ROLE FOR INSULIN RECEPTOR SUBSTRATE-1 IN THE NEUROTROPHIC ACTION OF N-METHYL-D-ASPARTATE AND ITS INHIBITION BY ETHANOL J. Biol. Chem., October 9, 1998; 273(41): 26596 - 26602. [Abstract] [Full Text] [PDF]

				R. J. Crowder and R. S. Freeman Glycogen Synthase Kinase-3beta Activity Is Critical for Neuronal Death Caused by Inhibiting Phosphatidylinositol 3-Kinase or Akt but Not for Death Caused by Nerve Growth Factor Withdrawal J. Biol. Chem., October 27, 2000; 275(44): 34266 - 34271. [Abstract] [Full Text] [PDF]