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Shp‐2 positively regulates brain‐derived neurotrophic factor‐promoted survival of cultured ventral mesencephalic dopaminergic neurons through a brain immunoglobulin‐like molecule with tyrosine‐based activation motifs/Shp substrate‐1
Author(s) -
Takai Satomi,
Yamada Masashi,
Araki Toshiyuki,
Koshimizu Hisatsugu,
Nawa Hiroyuki,
Hatanaka Hiroshi
Publication year - 2002
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.1471-4159.2002.00960.x
Subject(s) - neurotrophic factors , protein tyrosine phosphatase , brain derived neurotrophic factor , dopaminergic , biology , glial cell line derived neurotrophic factor , neurotrophin , microbiology and biotechnology , dephosphorylation , tyrosine hydroxylase , phosphatase , medicine , dopamine , endocrinology , signal transduction , phosphorylation , receptor , biochemistry
To examine the roles of Shp‐2, a cytoplasmic tyrosine phosphatase, in neuronal survival, we generated and used recombinant adenoviruses expressing wild type and phosphatase‐inactive (C/S), phosphatase domain‐deficient (delta P) and constitutively active (D61A and E76A) mutants of Shp‐2. We found that wild‐type Shp‐2 enhanced brain‐derived neurotrophic factor (BDNF)‐promoted survival of cultured ventral mesencephalic dopaminergic neurons. In contrast, the C/S and delta P mutants of Shp‐2 did not affect survival. In addition, the constitutively active D61A and E76A mutants mimicked BDNF and promoted survival. Furthermore, to examine the effects of BIT/SHPS‐1, a substrate of Shp‐2, on the BDNF‐promoted survival, we generated adenovirus vectors expressing wild‐type BIT/SHPS‐1 and its 4F mutant in which all tyrosine residues in the cytoplasmic domain of BIT/SHPS‐1 were replaced with phenylalanine. We found that BDNF‐promoted survival of cultured mesencephalic dopaminergic neurons was enhanced by expression of the 4F mutant but not of wild‐type BIT/SHPS‐1. In addition, we found that co‐expression of wild‐type BIT/SHPS‐1 with Shp‐2 significantly enhanced the survival‐promoting effect of BDNF on cultured mesencephalic dopaminergic neurons. These results indicated that Shp‐2 positively regulates the survival‐promoting effect of BDNF on cultured ventral mesencephalic dopaminergic neurons. Dephosphorylation of BIT/SHPS‐1 by Shp‐2 may participate in BDNF‐stimulated survival signaling.