Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling.
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.
Kang
David E
DE
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA. dekang@ucsd.edu
Yoon
Il Sang
IS
Repetto
Emanuela
E
Busse
Tracy
T
Yermian
Nader
N
Ie
Listya
L
Koo
Edward H
EH
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000502:physiology; D002460:Cell Line; D010450:Endopeptidases; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D053764:Presenilin-1; D053766:Presenilin-2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases; D048049:Extracellular Signal-Regulated MAP Kinases; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D053764:Presenilin-1; D053766:Presenilin-2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; C494918:AKT1 protein, human; C509280:BACE1 protein, human