The amyloid precursor protein and its network of interacting proteins: physiological and pathological implications

Aberrant phosphorylation in the pathogenesis of Alzheimer's disease

“…The short cytoplasmic C-terminal domain appears to play a central role in the structure and physiological function of APP. Interaction of the APP C-terminal domain with proteins such as X11/Mint and Fe65 affects APP processing either by stabilizing APP or by regulating Aβ production (77). The C-terminal domain of APP contains several residues shown to be phosphorylated by different protein kinases.…”

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

“…Phosphorylation of the GYENPTY motif of APP is not necessary for the binding of APP to most of its binding proteins that contain a PTB domain. The only exception to this is Shc, which requires the phosphorylation of Tyr682 for binding to APP [21,29]. Tyr682 phosphorylation is also necessary for the binding of APP to the SH2 domains of Abl and Grb2, and might regulate downstream signal transduction cascades [29,30].…”

“…The only exception to this is Shc, which requires the phosphorylation of Tyr682 for binding to APP [21,29]. Tyr682 phosphorylation is also necessary for the binding of APP to the SH2 domains of Abl and Grb2, and might regulate downstream signal transduction cascades [29,30]. Structural studies have revealed that the binding interface of APP and the PTB domain of X11 involves residues within the GYENPTY motif [31].…”

APP at a glance

“…In the case of G o and PAK3, this has been associated with FAD-linked APP mutations. Interaction of the APP tail with Shc and Grb2 is thought to lead to signaling through the Ras-Raf-MAPK pathway, and APP-Shc-Grb2 complexes have been reported to be increased in AD patients (Russo et al, 2005).…”

“…Phosphorylation of the intracellular tail is mediated by several kinases. These include the Ser/Thr kinases JNK, CDK5, GSK-3␤, which phosphorylate Thr668, and the non-receptor tyrosine kinases Abl and Src, and nerve growth factor tyrosinekinase receptor A (TrkA), which phosphorylate Tyr682 (Russo et al, 2005). Phosphorylation has been shown to regulate which proteins bind to the APP tail.…”