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Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling.
J Biol Chem. 2005 Sep 09; 280(36):31537-47.JB

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.

Authors+Show Affiliations

Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA. dekang@ucsd.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16014629

Citation

Kang, David E., et al. "Presenilins Mediate Phosphatidylinositol 3-kinase/AKT and ERK Activation Via Select Signaling Receptors. Selectivity of PS2 in Platelet-derived Growth Factor Signaling." The Journal of Biological Chemistry, vol. 280, no. 36, 2005, pp. 31537-47.
Kang DE, Yoon IS, Repetto E, et al. Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem. 2005;280(36):31537-47.
Kang, D. E., Yoon, I. S., Repetto, E., Busse, T., Yermian, N., Ie, L., & Koo, E. H. (2005). Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. The Journal of Biological Chemistry, 280(36), 31537-47.
Kang DE, et al. Presenilins Mediate Phosphatidylinositol 3-kinase/AKT and ERK Activation Via Select Signaling Receptors. Selectivity of PS2 in Platelet-derived Growth Factor Signaling. J Biol Chem. 2005 Sep 9;280(36):31537-47. PubMed PMID: 16014629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. AU - Kang,David E, AU - Yoon,Il Sang, AU - Repetto,Emanuela, AU - Busse,Tracy, AU - Yermian,Nader, AU - Ie,Listya, AU - Koo,Edward H, Y1 - 2005/07/13/ PY - 2005/7/15/pubmed PY - 2005/11/9/medline PY - 2005/7/15/entrez SP - 31537 EP - 47 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 280 IS - 36 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16014629/Presenilins_mediate_phosphatidylinositol_3_kinase/AKT_and_ERK_activation_via_select_signaling_receptors__Selectivity_of_PS2_in_platelet_derived_growth_factor_signaling_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16014629 DB - PRIME DP - Unbound Medicine ER -