PMID- 10646517 OWN - NLM STAT- MEDLINE DCOM- 20000210 LR - 20190630 IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 74 IP - 2 DP - 2000 Feb TI - Shp-2 specifically regulates several tyrosine-phosphorylated proteins in brain-derived neurotrophic factor signaling in cultured cerebral cortical neurons. PG - 659-68 AB - Brain-derived neurotrophic factor (BDNF), a member of the neurotrophins, promotes differentiation and survival and regulates plasticity of various types of neurons. BDNF binds to TrkB, a receptor tyrosine kinase, which results in the activation of a variety of signaling molecules to exert the various functions of BDNF. Shp-2, a Src homology 2 domain-containing cytoplasmic tyrosine phosphatase, is involved in neurotrophin signaling in PC12 cells and cultured cerebral cortical neurons. To examine the roles of Shp-2 in BDNF signaling in cultured rat cerebral cortical neurons, the wild-type and phosphatase-inactive mutant (C/S mutant) forms of Shp-2 were ectopically expressed in cultured neurons using recombinant adenovirus vectors. We found that several proteins tyrosine-phosphorylated in response to BDNF showed enhanced levels of tyrosine phosphorylation in cultured neurons infected with C/S mutant adenovirus in comparison with those infected with the wild-type Shp-2 adenovirus. In addition, in immunoprecipitates with anti-Shp-2 antibody, we also observed at least four proteins that displayed enhanced phosphorylation in response to BDNF in cultured neurons infected with the C/S mutant adenovirus. We found that the Shp-2-binding protein, brain immunoglobulin-like molecule with tyrosine-based activation motifs (BIT), was strongly tyrosine-phosphorylated in response to BDNF in cultured neurons expressing the C/S mutant of Shp-2. In contrast, the level of BDNF-induced phosphorylation of mitogen-activated protein kinase and coprecipitated proteins with anti-Trk and Grb2 antibodies did not show any difference between neurons infected with these two types of Shp-2. Furthermore, the survival effect of BDNF was enhanced by the wild type of Shp-2, although it was not influenced by the C/S mutant of Shp-2. These results indicated that in cultured cerebral cortical neurons Shp-2 is specifically involved in the regulation of several tyrosine-phosphorylated proteins, including BIT, in the BDNF signaling pathway. In addition, the phosphatase Shp-2 may not influence the level of BDNF-induced activation of mitogen-activated protein kinase in cultured cortical neurons. Further, Shp-2 may have potential to positively regulate BDNF-promoting neuronal survival. FAU - Araki, T AU - Araki T AD - Division of Protein Biosynthesis, Institute for Protein Research, Osaka University, Suita, Japan. FAU - Yamada, M AU - Yamada M FAU - Ohnishi, H AU - Ohnishi H FAU - Sano, S AU - Sano S FAU - Uetsuki, T AU - Uetsuki T FAU - Hatanaka, H AU - Hatanaka H LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Antigens, Differentiation) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (GRB2 Adaptor Protein) RN - 0 (Grb2 protein, rat) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Membrane Glycoproteins) RN - 0 (Neural Cell Adhesion Molecule L1) RN - 0 (Neural Cell Adhesion Molecules) RN - 0 (Phosphoproteins) RN - 0 (Proteins) RN - 0 (Receptors, Immunologic) RN - 42HK56048U (Tyrosine) RN - EC 2.7.10.1 (Receptor, trkA) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.1.3.2 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatases) RN - EC 3.1.3.48 (Ptpn11 protein, rat) RN - EC 3.1.3.48 (Ptpn6 protein, rat) SB - IM MH - *Adaptor Proteins, Signal Transducing MH - Animals MH - *Antigens, Differentiation MH - Brain-Derived Neurotrophic Factor/*physiology MH - Cells, Cultured MH - Cerebral Cortex/cytology/*metabolism MH - Enzyme Activation/physiology MH - Female MH - GRB2 Adaptor Protein MH - Intracellular Signaling Peptides and Proteins MH - Male MH - Membrane Glycoproteins/metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - Mutation/genetics/physiology MH - *Neural Cell Adhesion Molecule L1 MH - Neural Cell Adhesion Molecules/metabolism MH - Neurons/metabolism MH - Phosphoproteins/*metabolism MH - Phosphoric Monoester Hydrolases/metabolism MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11 MH - Protein Tyrosine Phosphatase, Non-Receptor Type 6 MH - Protein Tyrosine Phosphatases/genetics/*physiology MH - Proteins/metabolism MH - Rats MH - Rats, Wistar MH - Receptor, trkA/metabolism MH - Receptor, trkB/metabolism MH - *Receptors, Immunologic MH - Signal Transduction/*physiology MH - Tyrosine/*metabolism EDAT- 2000/01/26 00:00 MHDA- 2000/01/26 00:01 CRDT- 2000/01/26 00:00 PHST- 2000/01/26 00:00 [pubmed] PHST- 2000/01/26 00:01 [medline] PHST- 2000/01/26 00:00 [entrez] AID - 10.1046/j.1471-4159.2000.740659.x [doi] PST - ppublish SO - J Neurochem. 2000 Feb;74(2):659-68. doi: 10.1046/j.1471-4159.2000.740659.x.