Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex

Baki, Lia; Marambaud, Philippe; Efthimiopoulos, Spiros; Georgakopoulos, Anastasios; Wen, Paul; Cui, Wentao; Shioi, Junichi; Koo, Eduard; Ozawa, Masayuki; Friedrich, Victor L.; Robakis, Nikolaos K.

doi:10.1073/pnas.041603398

Cited by 179 publications

(180 citation statements)

References 41 publications

(56 reference statements)

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“…Decreased Rab7 was associated with increased g-secretase activity in early and mid MARY-X in vitro spheroidgenesis. However it had been suggested that increased g-secretase activity might dissociate E-cadherin, b-catenin, and a-catenin from the cytoskeleton, thus promoting disassembly of the E-cadherin-catenin adhesion complex, which might have negative effects on cell-cell adhesion (7,28). Thus, in the case of Mary-X well-formed spheroids, if increased g-secretase has negative effects on cell-cell adhesion, it would interfere with the formation of spheroids.…”

Section: Discussionmentioning

confidence: 99%

“…PS1, the catalytic subunit of g-secretase, reported to control g-secretase cleavage of E-cadherin (7), yields an N-terminal (PS1/NTF) and a C-terminal (PS1/ CTF) fragment. Following cleavage, the resultant PS1 fragments form a stable 1:1 heterodimer that binds to the cytoplasmic juxtamembrane region of E-cadherin (25)(26)(27)(28). For these reasons we measured PS1/NTF by Western blotting as a measurement of g-secretase activity.…”

Section: Discussionmentioning

confidence: 99%

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Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Yin

Gao

Tian

et al. 2012

Molecular Cancer Research

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The lymphovascular embolus is an enigmatic entity adept at metastatic dissemination and chemotherapy resistance. Using MARY-X, a human breast cancer xenograft that exhibits florid lymphovascular emboli in mice and spheroids in vitro, we established a model where the in vitro transition stages from minced tumoral aggregates to well-formed spheroids served as a surrogate for in vivo emboli formation. MARY-X well-formed spheroids and emboli exhibited strong similarity of expression. The aggregate-to-spheroid transition stages were characterized by increased ExoC5, decreased Hgs and Rab7, increased calpains, increased full-length E-cadherin (E-cad/FL), and the transient appearance of E-cad/NTF2, a 95 kDa E-cadherin fragment and increased Notch3icd (N3icd), the latter two fragments produced by increased g-secretase. Both transient and permanent knockdowns of Rab7 in MCF-7 cells increased protein but not transcription of E-cad/FL and resulted in the de novo appearance of E-cad/NTF2, the presence of nuclear E-cad/CTF2, and increased Notch1icd (N1icd). Overexpression of Rab7 conversely decreased E-cad/FL, g-secretase (PS1/NTF), and E-cad/NTF2. Overexpression of calpains did not alter PS1/NTF but decreased E-cad/FL and E-cad/NTF2 and increased N1icd. Well-formed spheroids showed increased Rab7, absent E-cad/NTF2, decreased PS1/NTF, increased E-cad/NTF1, and increased N3icd, the latter two fragments being the direct and indirect consequences, respectively, of increased calpains (calpain 1 and calpain 2). Inhibition of calpains decreased E-cad/NTF1 but increased E-cad/NTF2 showing that calpains compete with g-secretase (PS1) for closely located cleavage/binding sites on E-cadherin and that increased calpains can shuttle even decreased

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Yin

Gao

Tian

et al. 2012

Molecular Cancer Research

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“…The function of p120 ctn may further be modulated by presenilin through direct competition with p120 ctn for binding to cadherin (Baki et al, 2001;see Fig. 2).…”

Section: The Plot Regulatory Interactions At the Cytoplasmic Domain Omentioning

confidence: 99%

“…2). Presenilin also stimulates the interaction of E-cadherin with ␤-catenin and the cytoskeleton; the ultimate effect is to enhance adhesion (Baki et al, 2001;Georgakopoulos et al, 1999). The relationship between competition for binding of p120 ctn , enhanced binding of ␤-catenin to cadherin, and the interaction of presenilin with the cytosolic ␤-catenin complex (Murayama et al, 1998;Yu et al, 1998) remains to be clarified.…”

Section: The Plot Regulatory Interactions At the Cytoplasmic Domain Omentioning

confidence: 99%

Turn‐off, drop‐out: Functional state switching of cadherins

Lilien

Balsamo

Arregui

et al. 2002

Developmental Dynamics

149

116

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The classic cadherins are a group of calcium dependent, homophilic cell-cell adhesion molecules that drive morphogenetic rearrangements and maintain the integrity of cell groups through the formation of adherens junctions. The formation and maintenance of cadherin-mediated adhesions is a multistep process and mechanisms have evolved to regulate each step. This suggests that functional state switching plays an important role in development. Among the many challenges ahead is to determine the developmental role that functional state switching plays in tissue morphogenesis and to define the roles of each of the several regulatory interactions that participate in switching. One correlate of the loss of cadherinmediated adhesion, the "turn-off" of cadherin function, is the exit, or "drop-out" of cells from neural and epithelial layers and their conversion to a motile phenotype. We suggest that epithelial mesenchymal conversions may be initiated by signaling pathways that result in the loss of cadherin function. Tyrosine phosphorylation of ␤-catenin is one such mechanism. Enhanced phosphorylation of tyrosine residues on ␤-catenin is almost invariably associated with loss of the cadherin-actin connection concomitant with loss of adhesive function. There are several tyrosine kinases and phosphatases that have been shown to have the potential to alter the phosphorylation state of ␤-catenin and thus the function of cadherins. Our laboratory has focused on the role of the nonreceptor tyrosine phosphatase PTP1B in regulating the phosphorylation of ␤-catenin on tyrosine residues. Our data suggest that PTP1B is crucial for maintenance of N-cadherin-mediated adhesions in embryonic neural retina cells. By using an L-cell model system constitutively expressing N-cadherin, we have worked out many of the molecular interactions essential for this regulatory interaction. Extracellular cues that bias this critical regulatory interaction toward increased phosphorylation of ␤-catenin may be a critical component of many developmental events.

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“…Cell lines, transfections and transductions HEK293 and mouse glial C6 cells were grown in Dulbecco's modified Eagle's medium (DMEM) plus 10% fetal bovine serum (FBS) as described (Baki et al, 2001). All transfections were performed with 1 mg of cDNA using the Lipofectamine Plus TM Reagent (Invitrogen) according to manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Georgakopoulos¹,

Litterst²,

Ghersi³

et al. 2006

EMBO J

Self Cite

146

178

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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.

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Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex

Cited by 179 publications

References 41 publications

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Early to Intermediate Steps of Tumor Embolic Formation Involve Specific Proteolytic Processing of E-Cadherin Regulated by Rab7

Turn‐off, drop‐out: Functional state switching of cadherins

Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

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