Abstract
The Alzheimer's disease-linked genes, PS1 and PS2, are required for intramembrane proteolysis of multiple type I proteins, including Notch and amyloid precursor protein. In addition, it has been documented that PS1 positively regulates, whereas PS1 familial Alzheimer disease mutations suppress, phosphatidylinositol 3-kinase (PI3K)/Akt activation, a pathway known to inactivate glycogen synthase kinase-3 and reduce tau phosphorylation. In this study, we show that the loss of presenilins not only inhibits PI3K/Akt signaling and increases tau phosphorylation but also suppresses the MEK/ERK pathway. The deficits in Akt and ERK activation in cells deficient in both PS1 and PS2 (PS-/-) are evident after serum withdrawal and stimulation with fetal bovine serum or ligands of select receptor tyrosine kinases, platelet-derived growth factor receptor beta (PDGFR beta) and PDGFR alpha, but not insulin-like growth factor-1R and epidermal growth factor receptor. The defects in PDGF signaling in PS-/- cells are due to reduced expression of PDGF receptors. Whereas fetal bovine serum-induced Akt activation is reconstituted by both PS1 and PS2 in PS-/- cells, PDGF signaling is selectively restored by PS2 but not PS1 and is dependent on the N-terminal fragment of PS2 but not gamma-secretase activity or the hydrophilic loop of PS2. The rescue of PDGF receptor expression and activation by PS2 is facilitated by FHL2, a PS2-interacting transcriptional co-activator. Finally, we present evidence that PS1 mutations interfere with this PS2-mediated activity by reducing PS2 fragments. These findings highlight important roles of both presenilins in Akt and ERK signaling via select signaling receptors.
Highlights
The Alzheimerâs disease-linked genes, PS1 and PS2, are required for intramembrane proteolysis of multiple type I proteins, including Notch and amyloid precursor protein
Loss of Presenilins Impairs phosphatidylinositol 3-kinase (PI3K)/Akt and ERK Signaling, Elevates glycogen synthase kinase-3 (GSK-3) Activity, and Increases Tau PhosphorylationâWe previously demonstrated that presenilin plays an important role in promoting the degradation of â€-catenin, a key signaling intermediate in the Wnt signaling pathway, by acting as a scaffold upon which GSK-3, â€-catenin, and a priming kinase are brought together to facilitate the stepwise phosphorylation of â€-catenin [16]
Because PI3K/Akt activation is principally generated by cell surface receptor tyrosine kinase (RTK) that signal through the MEK/ERK mitogen-activated protein kinase pathway, we examined whether the activation of ERK is affected by the loss of presenilins
Summary
The Alzheimerâs disease-linked genes, PS1 and PS2, are required for intramembrane proteolysis of multiple type I proteins, including Notch and amyloid precursor protein. It has been documented that PS1 positively regulates, whereas PS1 familial Alzheimer disease mutations suppress, phosphatidylinositol 3-kinase (PI3K)/Akt activation, a pathway known to inactivate glycogen synthase kinase-3 and reduce tau phosphorylation. In addition to their roles in A†production and Notch proteolysis, presenilins have been shown to mediate other physiological activities in vitro and Alzheimer disease; APP, amyloid precursor protein; RTK, receptor tyrosine kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; ERK, extracellular signal-regulated kinase; GSK-3, glycogen synthase kinase-3; PI3K, phosphatidylinositol 3-kinase; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; IGF, insulin-like growth factor; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; DMEM, Dulbeccoâs modified Eagleâs medium; FBS, fetal bovine serum; siRNA, small interfering RNA; RT, reverse transcription; CTF, C-terminal fragment; NTF, N-terminal fragment; CREB, cAMPresponse element-binding protein; CBP, CREB-binding protein. We hypothesized that select upstream cell surface signaling receptors are affected by presenilin activity rather than downstream signaling components
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