TY - JOUR
T1 - APP is Phosphorylated by TrkA and regulates NGF/TrkA signaling
AU - Matrone, Carmela
AU - Barbagallo, Alessia P.M.
AU - La Rosa, Luca R.
AU - Florenzano, Fulvio
AU - Ciotti, Maria T.
AU - Mercanti, Delio
AU - Chao, Moses V.
AU - Calissano, Pietro
AU - D'Adamio, Luciano
PY - 2011/8/17
Y1 - 2011/8/17
N2 - The pathogenic model of Alzheimer's disease (AD) posits that aggregates of amyloid β, a product of amyloid precursor protein (APP) processing, cause dementia. However, alterations of normal APP functions could contribute to AD pathogenesis, and it is therefore important to understand the role of APP. APP is a member of a gene family that shows functional redundancy as documented by the evidence that single knock-out mice are viable, whereas mice with combined deletions of APP family genes die shortly after birth. A residue in the APP intracellular region, Y682, is indispensable for these essential functions of APP. It is therefore important to identify pathways that regulate phosphorylation of Y682 as well as the role of Y682 in vivo. TrkA is associated with both phosphorylation of APP-Y682 and alteration of APP processing, suggesting that tyrosine phosphorylation of APP links APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival. Here we have tested whether the NGF/TrkA signaling pathway is a physiological regulator of APP phosphorylation. We find that NGF induces tyrosine phosphorylation of APP, and that APP interacts with TrkA and this interaction requires Y682. Unpredictably, we also uncover that APP, and specifically Y682, regulates activation of the NGF/TrkA signaling pathway in vivo, the subcellular distribution of TrkA and the sensitivity of neurons to the trophic action of NGF. This evidence suggests that these two membrane protein's functions are strictly interconnected and that the NGF/TrkA signaling pathway is involved in AD pathogenesis and can be used as a therapeutic target.
AB - The pathogenic model of Alzheimer's disease (AD) posits that aggregates of amyloid β, a product of amyloid precursor protein (APP) processing, cause dementia. However, alterations of normal APP functions could contribute to AD pathogenesis, and it is therefore important to understand the role of APP. APP is a member of a gene family that shows functional redundancy as documented by the evidence that single knock-out mice are viable, whereas mice with combined deletions of APP family genes die shortly after birth. A residue in the APP intracellular region, Y682, is indispensable for these essential functions of APP. It is therefore important to identify pathways that regulate phosphorylation of Y682 as well as the role of Y682 in vivo. TrkA is associated with both phosphorylation of APP-Y682 and alteration of APP processing, suggesting that tyrosine phosphorylation of APP links APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival. Here we have tested whether the NGF/TrkA signaling pathway is a physiological regulator of APP phosphorylation. We find that NGF induces tyrosine phosphorylation of APP, and that APP interacts with TrkA and this interaction requires Y682. Unpredictably, we also uncover that APP, and specifically Y682, regulates activation of the NGF/TrkA signaling pathway in vivo, the subcellular distribution of TrkA and the sensitivity of neurons to the trophic action of NGF. This evidence suggests that these two membrane protein's functions are strictly interconnected and that the NGF/TrkA signaling pathway is involved in AD pathogenesis and can be used as a therapeutic target.
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U2 - 10.1523/JNEUROSCI.1960-11.2011
DO - 10.1523/JNEUROSCI.1960-11.2011
M3 - Article
C2 - 21849536
AN - SCOPUS:80051756788
SN - 0270-6474
VL - 31
SP - 11756
EP - 11761
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 33
ER -