The generation of biologically active proteins by regulated intramembrane proteolysis is a highly conserved mechanism in cell signaling. Presenilin-dependent ␥-secretase activity is responsible for the intramembrane proteolysis of selected type I membrane proteins, including ␤-amyloid precursor protein (APP) and Notch. A small fraction of intracellular domains derived from both APP and Notch translocates to and appears to function in the nucleus, suggesting a generic role for ␥-secretase cleavage in nuclear signaling. Here we show that the p75 neurotrophin receptor (p75 NTR ) undergoes presenilin-dependent intramembrane proteolysis to yield the soluble p75-intracellular domain. The p75 NTR is a multifunctional type I membrane protein that promotes neurotrophininduced neuronal survival and differentiation by forming a heteromeric co-receptor complex with the Trk receptors. Mass spectrometric analysis revealed that ␥-secretase-mediated cleavage of p75 NTR occurs at a position located in the middle of the transmembrane (TM) domain, which is reminiscent of the amyloid ␤-peptide 40 (A␤40) cleavage of APP and is topologically distinct from the major TM cleavage site of Notch 1. Size exclusion chromatography and co-immunoprecipitation analyses revealed that TrkA forms a molecular complex together with either full-length p75 or membrane-tethered C-terminal fragments. The p75-ICD was not recruited into the TrkAcontaining high molecular weight complex, indicating that ␥-secretase-mediated removal of the p75 TM domain may perturb the interaction with TrkA. Independent of the possible nuclear function, our studies suggest that ␥-secretase-mediated p75 NTR proteolysis plays a role in the formation/disassembly of the p75-TrkA receptor complex by regulating the availability of the p75 TM domain that is required for this interaction.The p75 neurotrophin receptor (p75 NTR

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 2؉ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP 2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid ␤-peptide (A␤42) levels. Our data suggest that PIP 2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A␤42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP 2 may offer a therapeutic approach in Alzheimer's disease.␤-amyloid precursor protein ͉ channel ͉ secretase ͉ transient receptor potential melastatin 7 (TRPM7) ͉ capacitative calcium entry

Background: Loss or mutation of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF2R) has been found in breast cancer. However, whether or not decreased levels of functional M6P/IGF2R directly contribute to the process of carcinogenesis needs to be further verified by functional studies.

Background:Cerebral elevation and accumulation of amyloid ␤-peptide is an invariant feature of Alzheimer disease. Results: Natural compound (20S)-Rg3, a PI4KII␣ activator, modulates ␥-secretase activity in lipid rafts by increasing levels of phosphoinositides. Conclusion: Activation of a key phospholipid synthetic pathway by a natural product regulates ␥-secretase activity. Significance: We identify a novel molecular mechanism for the regulation of ␥-secretase activity by (20S)-Rg3.