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Brain‐Derived Neurotrophic Factor Stimulates Interactions of Shp2 with Phosphatidylinositol 3‐Kinase and Grb2 in Cultured Cerebral Cortical Neurons
Author(s) -
Yamada Masashi,
Ohnishi Hiroshi,
Sano Shinichiro,
Araki Toshiyuki,
Nakatani Atsushi,
Ikeuchi Toshihiko,
Hatanaka Hiroshi
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0730041.x
Subject(s) - tropomyosin receptor kinase b , neurotrophic factors , grb2 , brain derived neurotrophic factor , microbiology and biotechnology , neurotrophin , protein tyrosine phosphatase , trk receptor , phosphorylation , signal transduction , tyrosine phosphorylation , chemistry , biology , neuroscience , proto oncogene tyrosine protein kinase src , receptor , biochemistry
Abstract: Shp2, a protein tyrosine phosphatase possessing SH2 domains, is utilized in the intracellular signaling of various growth factors. Shp2 is highly expressed in the CNS. Brain‐derived neurotrophic factor (BDNF), a member of the neurotrophin family, which also shows high levels of expression in the CNS, exerts neurotrophic and neuromodulatory effects in CNS neurons. We examined how BDNF utilizes Shp2 in its signaling pathway in cultured cerebral cortical neurons. We found that BDNF stimulated coprecipitation of several tyrosinephosphorylated proteins with anti‐Shp2 antibody and that Grb2 and phosphatidylinositol 3‐kinase (PI3‐K) were coprecipitated with anti‐Shp2 antibody in response to BDNF. In addition, both anti‐Grb2 and anti‐PI3‐K antibodies coprecipitated Shp2 in response to BDNF. The BDNF‐stimulated coprecipitation of the tyrosine‐phosphorylated proteins, Grb2, and PI3‐K with anti‐Shp2 antibody was completely inhibited by K252a, an inhibitor of TrkB receptor tyrosine kinase. This BDNF‐stimulated Shp2 signaling was markedly sustained as well as BDNF‐induced phosphorylation of TrkB and mitogen‐activated protein kinases. In PC12 cells stably expressing TrkB, both BDNF and nerve growth factor stimulated Shp2 signaling similarly to that by BDNF in cultured cortical neurons. These results indicated that Shp2 shows cross‐talk with various signaling molecules including Grb2 and PI3‐K in BDNF‐induced signaling and that Shp2 may be involved in the regulation of various actions of BDNF in CNS neurons.