Journal of Biological Chemistry
Volume 280, Issue 36, 9 September 2005, Pages 31537-31547
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Mechanisms of Signal Transduction
Presenilins Mediate Phosphatidylinositol 3-Kinase/AKT and ERK Activation via Select Signaling Receptors: SELECTIVITY OF PS2 IN PLATELET-DERIVED GROWTH FACTOR SIGNALING*

https://doi.org/10.1074/jbc.M500833200Get rights and content
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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 β (PDGFRβ) and PDGFRα, 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 γ-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.

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*

This work was supported in part by the American Federation for Aging Research (to D. E. K.) and Alzheimer's Association Grant NIRG-02-4044 (to D. E. K.). Parts of this paper were presented at the 9th International Conference on Alzheimer's Disease and Related Disorders, July 17–22, 2004, Philadelphia, and published in abstract form (54). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.