RRC ID 12177
Author Araki T, Yamada M, Ohnishi H, Sano S, Uetsuki T, Hatanaka H.
Title Shp-2 specifically regulates several tyrosine-phosphorylated proteins in brain-derived neurotrophic factor signaling in cultured cerebral cortical neurons.
Journal J Neurochem
Abstract 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.
Volume 74(2)
Pages 659-68
Published 2000-2-1
DOI 10.1046/j.1471-4159.2000.740659.x
PMID 10646517
MeSH Adaptor Proteins, Signal Transducing* Animals Antigens, Differentiation* Brain-Derived Neurotrophic Factor / physiology* Cells, Cultured Cerebral Cortex / cytology Cerebral Cortex / metabolism* Enzyme Activation / physiology Female GRB2 Adaptor Protein Intracellular Signaling Peptides and Proteins Male Membrane Glycoproteins / metabolism Mitogen-Activated Protein Kinases / metabolism Mutation / genetics Mutation / physiology Neural Cell Adhesion Molecule L1* Neural Cell Adhesion Molecules / metabolism Neurons / metabolism Phosphoproteins / metabolism* Phosphoric Monoester Hydrolases / metabolism Protein Tyrosine Phosphatase, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Non-Receptor Type 6 Protein Tyrosine Phosphatases / genetics Protein Tyrosine Phosphatases / physiology* Proteins / metabolism Rats Rats, Wistar Receptor, trkA / metabolism Receptor, trkB / metabolism Receptors, Immunologic* Signal Transduction / physiology* Tyrosine / metabolism*
IF 4.066
Times Cited 27
DNA material AxCANCre (RDB01748) AxCALacZ Adex1CAlacZ (RDB02726)