E-cadherin controls a wide array of cellular behaviors including cell-cell adhesion, differentiation and tissue development. Here we show that presenilin-1 (PS1), a protein involved in Alzheimer's disease, controls a gamma-secretase-like cleavage of E-cadherin. This cleavage is stimulated by apoptosis or calcium influx and occurs between human E-cadherin residues Leu731 and Arg732 at the membrane-cytoplasm interface. The PS1/gamma-secretase system cleaves both the full-length E-cadherin and a transmembrane C-terminal fragment, derived from a metalloproteinase cleavage after the E-cadherin ectodomain residue Pro700. The PS1/gamma-secretase cleavage dissociates E-cadherins, beta-catenin and alpha-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex. Furthermore, this cleavage releases the cytoplasmic E-cadherin to the cytosol and increases the levels of soluble beta- and alpha-catenins. Thus, the PS1/gamma-secretase system stimulates disassembly of the E-cadherin- catenin complex and increases the cytosolic pool of beta-catenin, a key regulator of the Wnt signaling pathway.

SUMMARY G protein-coupled receptors form hetero-dimers and higher order hetero-oligomers, yet the significance of receptor heteromerization in cellular and behavioral responses is poorly understood. Atypical antipsychotic drugs, such as clozapine and risperidone all have in common a high affinity for the serotonin 5-HT2A receptor (2AR). However, closely related nonantipsychotic drugs, such as ritanserin and methysergide, while blocking 2AR function, lack comparable neuropsychological effects. Why some but not all drugs that inhibit 2AR-dependent signaling exhibit antipsychotic properties remains unresolved. We found that a heteromeric complex formed between the metabotropic glutamate 2 receptor (mGluR2) and the 2AR critically integrates the action of drugs affecting signaling and behavioral outcomes. Acting through the mGluR2/2AR heterocomplex, both glutamatergic and serotonergic drugs achieve a balance between Gi- and Gq-dependent signaling that predicts their psychoactive behavioral effects. These observations provide a novel mechanistic insight into antipsychotic action that may advance therapeutic strategies for schizophrenia.

Phosphatidylinositol 3-kinase (PI3K) promotes cell survival and communication by activating its downstream effector Akt kinase. Here we show that PS1, a protein involved in familial Alzheimer's disease (FAD), promotes cell survival by activating the PI3K/Akt cell survival signaling. This function of PS1 is unaffected by c-secretase inhibitors. Pharmacological and genetic evidence indicates that PS1 acts upstream of Akt, at or before PI3K kinase. PS1 forms complexes with the p85 subunit of PI3K and promotes cadherin/PI3K association. Furthermore, conditions that inhibit this association prevent the PS1-induced PI3K/Akt activation, indicating that PS1 stimulates PI3K/Akt signaling by promoting cadherin/PI3K association. By activating PI3K/Akt signaling, PS1 promotes phosphorylation/inactivation of glycogen synthase kinase-3 (GSK-3), suppresses GSK-3-dependent phosphorylation of tau at residues overphosphorylated in AD and prevents apoptosis of confluent cells. PS1 FAD mutations inhibit the PS1-dependent PI3K/Akt activation, thus promoting GSK-3 activity and tau overphosphorylation at ADrelated residues. Our data raise the possibility that PS1 may prevent development of AD pathology by activating the PI3K/Akt signaling pathway. In contrast, FAD mutations may promote AD pathology by inhibiting this pathway. IntroductionIncreased neuronal cell death, tau overphosphorylation and accumulation of neurofibrillary tangles (NFTs) and amyloid plaques are the main pathological hallmarks of Alzheimer's disease (AD) brains. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays crucial roles in the transmission of survival signals in a wide range of cell types including neurons (for reviews, see Chan et al, 1999;Brunet et al, 2001). PI3K activates its downstream effector Akt/protein kinase B (Akt) by promoting its phosphorylation at residues serine 473 (Ser473) and threonine 308 (Thr308). Activated Akt, in turn, phosphorylates a wide range of substrates activating anti-apoptotic (survival) factors and inactivating pro-apoptotic factors (Brunet et al, 2001). The PI3K/Akt pathway is activated following recruitment of PI3K to the plasma membrane in response to a number of extracellular stimuli including growth factors (Brunet et al, 2001) and cadherin homophilic cell-cell adhesions, which result in the recruitment of PI3K to adhesion complexes (Pece et al, 1999;Kovacs et al, 2002;Tran et al, 2002;Yap and Kovacs, 2003). Akt downregulates the activities of glycogen synthase kinases 3a (GSK-3a) and 3b (GSK-3b) by phosphorylating the former at residue serine 21 (Ser21) and the latter at residue serine 9 (Ser9) (Cross et al, 1995;Kaytor and Orr, 2002). Increased GSK-3b activity has been implicated in neuronal cell death (Pap and Cooper, 1998;Hetman et al, 2000;Cross et al, 2001;Lucas et al, 2001) and tau overphosphorylation (Hanger et al, 1992;Hong et al, 1997;Pei et al, 1999;Lucas et al, 2001), while GSK-3a was recently implicated in the production of Ab peptide, the principal protein component of amyloid plaques (Phiel et...

Bidirectional signaling triggered by interacting ephrinB receptors (EphB) and ephrinB ligands is crucial for development and function of the vascular and nervous systems. A signaling cascade triggered by this interaction involves activation of Src kinase and phosphorylation of ephrinB. The mechanism, however, by which EphB activates Src in the ephrinB-expressing cells is unknown. Here we show that EphB stimulates a metalloproteinase cleavage of ephrinB2, producing a carboxy-terminal fragment that is further processed by PS1/c-secretase to produce intracellular peptide ephrinB2/CTF2. This peptide binds Src and inhibits its association with inhibitory kinase Csk, allowing autophosphorylation of Src at residue tyr418. EphrinB2/CTF2-activated Src phosphorylates ephrinB2 and inhibits its processing by c-secretase. These data show that the PS1/c-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, csecretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and c-secretase dominant-negative mutants inhibited the EphB-induced cleavage of ephrinB2 and Src autophosphorylation, raising the possibility that FAD mutants interfere with the functions of Src and ephrinB2 in the CNS.