Involvement of presenilins in cell-survival signalling pathways

Abstract

Familial AD (Alzheimer's disease) is a rare autosomal dominant form of AD, associated with clinical and pathological features similar to those identified in the more prevalent sporadic AD cases. The majority of familial AD cases are caused by mutations in either of the highly homologous PS (presenilins), an essential component of the gamma-secretase enzyme complex, or amyloid precursor protein, a gamma-secretase substrate and the precursor of amyloid beta peptides. The observation that PS are absolutely required for gamma-secretase activity, and parallel studies demonstrating that PS interact with several signalling molecules, modulate their stability or regulate their proteolysis, have led to the suggestion that involvement of PS in additional signalling pathways mediating key cellular functions may contribute to the pathogenesis and progression of neurodegeneration. In this paper, we review PS-regulated molecules, their role in cell signalling and possible involvement in neurodegeneration in patients suffering from AD.

Heterogeneity of Jagged1 expression in human and mouse intestinal tumors: implications for targeting Notch signaling

“…However, it was interesting that inhibition of Notch signaling with GSI inhibited the proliferation and induced the expression of secretory markers, whereas downregulating Notch by simultaneously targeting Notch1 and Notch2 with an siRNA approach, or Jagged1, was sufficient to induce the markers of goblet cell differentiation, but failed to alter the proliferation of the HT29Cl16E cells. Similar discrepancies were observed between GSI treatment and Notch/RBP/Jk pathway silencing in taxane-induced mitotic arrest in colon cancer cells (Akiyoshi et al, 2008), suggesting that other targets of g-secretase activity (McCarthy, 2005) might be involved in cell-cycle regulation of HT29Cl16E colon cancer cells. This may be related to the recent report that cells respond to a Notch-dependent mitogenic stimulus only when the Wnt cascade is intact, but that the effect of Notch on cell differentiation is independent of Wnt (Fre et al, 2009).…”

HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation

“…Thus, it is tempting to speculate that presenilin C termini could regulate the association of HtrA2 with the ER membranes. This could also be relevant regarding the role of cytosolic HtrA2 in apoptosis, especially in light of the antiapoptotic roles attributed to presenilin C-terminal fragments (54). Interestingly, proteolytic activity of HtrA2 can be regulated through phosphorylation at S212 by Akt kinase, a member of a key antiapoptotic pathway, adding another layer of complexity to HtrA2 biology (55).…”

Interleukin-1 Receptor Type 1 Is a Substrate for γ-Secretase-dependent Regulated Intramembrane Proteolysis

“…We demonstrate that ␥-secretase is capable of catalyzing the proteolytic cleavage of membrane-anchored fragments of ectodomainshed IL-1R1 to generate the IL-1R1-ICD. The ␥-secretase complex is responsible for the proteolytic cleavage of at least 50 substrates (34,39,113). Limited homology among the putative cleavage sites of known ␥-secretase substrates demonstrates that the intramembrane cleavage event is not dependent on strict amino acid sequence specificity.…”

“…In other cases, studies demonstrate that subsequent to ectodomain shedding, intramembrane proteolysis initiates degradation of the membrane spanning domains of receptors or termination of receptor-signaling functions (35,57). Independent of ␥-secretase activities, through specific protein-protein interactions the presenilins have also been implicated in several intracellular processes, including cell adhesion (58), regulation of calcium homeostasis (59), trafficking of select membrane proteins and/or intracellular vesicles (60,61), Wnt/␤-catenin signaling (62), and neuronal plasticity (36,39). These functions have been corroborated by reports of defective signal transduction in cells lacking presenilin proteins, where loss of presenilins affect ␤-catenin (63), phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase kinase/extracellular signalregulated kinase (ERK) (64), stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) (65), and B cell receptor signaling (50).…”