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

Satomi Takai, Masashi Yamada, Toshiyuki Araki, Hisatsugu Koshimizu, Hiroyuki Nawa, Hiroshi Hatanaka

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Abstract

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.

Original languageEnglish
Pages (from-to)353-364
Number of pages12
JournalJournal of Neurochemistry
Volume82
Issue number2
DOIs
Publication statusPublished - 25-07-2002

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Dopaminergic Neurons
Brain-Derived Neurotrophic Factor
Neurons
Tyrosine
Immunoglobulins
Brain
Chemical activation
Molecules
Substrates
Phosphoric Monoester Hydrolases
Adenoviridae
Phenylalanine
2-(4-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidazole

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

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title = "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",
abstract = "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.",
author = "Satomi Takai and Masashi Yamada and Toshiyuki Araki and Hisatsugu Koshimizu and Hiroyuki Nawa and Hiroshi Hatanaka",
year = "2002",
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T1 - 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

AU - Takai, Satomi

AU - Yamada, Masashi

AU - Araki, Toshiyuki

AU - Koshimizu, Hisatsugu

AU - Nawa, Hiroyuki

AU - Hatanaka, Hiroshi

PY - 2002/7/25

Y1 - 2002/7/25

N2 - 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.

AB - 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.

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