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Regulation of β‐amyloid precursor protein expression by brain‐derived neurotrophic factor involves activation of both the Ras and phosphatidylinositide 3‐kinase signalling pathways
Author(s) -
RuizLeón Yolanda,
Pascual Angel
Publication year - 2004
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.1471-4159.2003.02226.x
Subject(s) - tropomyosin receptor kinase b , wortmannin , neurotrophic factors , pi3k/akt/mtor pathway , ly294002 , brain derived neurotrophic factor , microbiology and biotechnology , mapk/erk pathway , signal transduction , protein kinase b , biology , neurotrophin , chemistry , receptor , biochemistry
Brain‐derived neurotrophic factor (BDNF) stimulates β‐amyloid precursor protein (APP) promoter activity by a Ras‐dependent mechanism in TrkB‐expressing SH‐SY5Y cells. To determine the signalling pathways involved in the BDNF‐induced response, we have analysed the ability of TrkB mutated forms to mediate promoter stimulation. Brain‐derived neurotrophic factor causes a significant induction of promoter activity and mutation K540R in the active site of TrkB completely abolishes the neurotrophin‐induced response. A substitution of the Y484 residue by phenylalanine, which blocks binding of Shc, reduces the activation of APP promoter by BDNF by approximately 50% whereas mutation Y785P, which blocks binding of phospholipase C gamma, does not affect the response. In addition, the phosphatidylinositide 3‐kinase (PI3K)‐specific inhibitors wortmannin and LY294002 reduced BDNF‐induced activation. In agreement with a participation of both Ras/MAPK‐ and PI3K/Akt‐mediated mechanisms, transient expression of constitutive active forms of Ras, PI3K and other components of both signalling pathways led to a significant increase of APP promoter activity. Furthermore, the stimulation of the APP promoter by BDNF was completely precluded by expression of dominant‐negative forms of Ras and PI3K effectors. Taken together, our results suggest that simultaneous activation of at least two signalling pathways, Ras/MAPK and PI3K/Akt, is necessary to mediate a full activation of the APP promoter by BDNF.