Novel GαS-protein signaling associated with membrane-tethered amyloid precursor protein intracellular domain.
Numerous physiological functions, including a role as a cell surface receptor, have been ascribed to Alzheimer's disease-associated amyloid precursor protein (APP). However, detailed analysis of intracellular signaling mediated by APP in neurons has been lacking. Here, we characterized intrinsic signaling associated with membrane-bound APP C-terminal fragments, which are generated following APP ectodomain release by α- or β-secretase cleavage. We found that accumulation of APP C-terminal fragments or expression of membrane-tethered APP intracellular domain results in adenylate cyclase-dependent activation of PKA (protein kinase A) and inhibition of GSK3β signaling cascades, and enhancement of axodendritic arborization in rat immortalized hippocampal neurons, mouse primary cortical neurons, and mouse neuroblastoma. We discovered an interaction between BBXXB motif of APP intracellular domain and the heterotrimeric G-protein subunit Gα(S), and demonstrate that Gα(S) coupling to adenylate cyclase mediates membrane-tethered APP intracellular domain-induced neurite outgrowth. Our study provides clear evidence that APP intracellular domain can have a nontranscriptional role in regulating neurite outgrowth through its membrane association. The novel functional coupling of membrane-bound APP C-terminal fragments with Gα(S) signaling identified in this study could impact several brain functions such as synaptic plasticity and memory formation.
Department of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, Illinois 60637, USA.
Carole
C
Deyts
Kulandaivelu S
KS
Vetrivel
Shibandri
S
Das
Yumiko M
YM
Shepherd
Denis J
DJ
Dupré
Gopal
G
Thinakaran
Angèle T
AT
Parent
D000262:Adenylyl Cyclases / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000737:chemistry / Q000502:physiology*; D007425:Intracellular Membranes / Q000737:chemistry / Q000502:physiology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016501:Neurites / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases