A core function for p120-catenin in cadherin turnover

Davis, Michael A.; Ireton, Reneé C.; Reynolds, Albert B.

doi:10.1083/jcb.200307111

Cited by 663 publications

(756 citation statements)

References 45 publications

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“…29,30,33 Therefore, we investigated whether loss of p120 association with mutant E-cadherin lead to increased interaction with Hakai. Although the expression levels of Hakai remain unchanged (Figure 3c), we verified that E-cadherin mutations that block p120 association, those located at p120 binding domain, resulted in a significant increase of the interplay with Hakai: 1.84-fold for R749W (P ¼ 0.027), 2.29-fold for E757K and 1.73-fold for E781D (P ¼ 0.036) (Figures 3a and b).…”

Section: Resultsmentioning

confidence: 99%

“…23 The p120-catenin is the best known inhibitor of cadherin endocytosis, as its binding to the E-cadherin juxtamembrane domain is required for maintenance and stability of E-cadherin molecules at the PM and, simultaneously, it physically blocks the interaction with proteins from the endocytic machinery, such as clathrin adaptor proteins and Hakai. [29][30][31][32][33] Importantly, Hakai binds directly to E-cadherin and, being an E3 ubiquitin ligase, it ubiquitinates and induces E-cadherin endocytosis. 33 Taking into account the present knowledge about E-cadherin regulation, we tested whether and how the E-cadherin cytoplasmic mutations interfere with key trafficking-related partners, leading to abnormal E-cadherin expression, localization and function, supporting their pathogenic relevance.…”

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 99%

“…27,28 At the PM, p120-catenin binds to the cadherin juxtamembrane domain, stabilizing and preventing the entry of E-cadherin into degradative endocytic pathways. [29][30][31][32] E-cadherin deprived of p120 is prone to interact with other proteins, such as clathrin adapter proteins and Hakai, promoting E-cadherin internalization. 32,33 After internalization, E-cadherin can be recycled back to the PM or targeted for degradation.…”

Section: Introductionmentioning

confidence: 99%

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The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

et al. 2012

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In hereditary diffuse gastric cancer (HDGC), CDH1 germline gene alterations are causative events in 30% of the cases. In 20% of HDGC families, CDH1 germline mutations are of the missense type and the mutation carriers constitute a problem in terms of genetic counseling and surveillance. To access the pathogenic relevance of missense mutations, we have previously developed an in vitro method to functionally characterize them. Pathogenic E-cadherin missense mutants fail to aggregate and become more invasive, in comparison with cells expressing the wild-type (WT) protein. Herein, our aim was to develop a complementary method to unravel the pathogenic significance of E-cadherin missense mutations. We used cells stably expressing WT E-cadherin and seven HDGC-associated mutations (five intracellular and two extracellular) and studied by proximity ligation assays (PLA) how these mutants bind to fundamental regulators of E-cadherin function and trafficking. We focused our attention on the interaction with: p120, b-catenin, PIPKIc and Hakai. We showed that cytoplasmic E-cadherin mutations affect the interaction of one or more binding partners, compromising the E-cadherin stability at the plasma membrane and likely affecting the adhesion complex competence. In the present work, we demonstrated that the study of the interplay between E-cadherin and its binding partners, using PLA, is an easy, rapid, quantitative and highly reproducible technique that can be applied in routine labs to verify the pathogenicity of E-cadherin missense mutants for HDGC diagnosis, especially those located in the intracellular domain of the protein. Keywords: HDGC; E-cadherin; CDH1 mutations; E-cadherin trafficking; E-cadherin binding partners; diagnostic method INTRODUCTIONHereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome characterized by a high risk of developing diffuse gastric cancer 1-3 and lobular breast cancer 4-6 during life-time. CDH1 germline gene alterations (mutations or deletions), resulting in E-cadherin inactivation, are the only causative events described till now and were identified in approximately 30% of HDGC cases. 2,3,7 To date, 122 different germline mutations have been described in these families, 8 being the majority of them of the nonsense type, leading to alternative premature termination codons. 3 This type of CDH1 mutant transcripts is commonly downregulated by nonsensemediated decay leading to E-cadherin loss of function 9 and these patients are considered high-risk carriers and are counseled to perform prophylactic total gastrectomy. 10 In about 20% of HDGC families, carriers show CDH1 germline missense mutations 11 and, in contrast to truncating mutations, their pathogenic significance is not straightforward, therefore constituting a problem in terms of genetic counseling and surveillance.In 2004, Fitzgerald and Caldas 10 suggested that the significance of CDH1 missense mutations should be assessed in at least four affected members within a HDGC family in combination with functional and

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Section: Resultsmentioning

confidence: 99%

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

et al. 2012

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“…If p120 at the cell-surface regulates cadherin levels by controlling cadherin turnover [7], we could expect that modifications to p120 such as serine/threonine phosphorylation might influence cadherin stability at the cell-surface. Since increased E-cadherin trafficking occurs in response to weakening or disrupting cell-cell adhesion [44], we treated S2-013 3A and S2-013 4A cells with EGTA and found that E-cadherin underwent faster degradation in S2-013 4A cells than in S2-013 3A cells (not shown).…”

Section: A Role For P120 Regulatory Domain In Stabilizing E-cadherinmentioning

confidence: 99%

“…p120 has multiple biological functions including regulation of cell adhesion by controlling cadherin turnover at the cell surface [7]. Cells expressing Ecadherin with a defective p120 binding site (764EED/AAA) failed to recruit p120 into the cadherin-catenin complex, and have reduced cell-cell adhesion, highlighting the importance of p120 in cadherin function [8].…”

Section: Introductionmentioning

confidence: 99%

The regulatory or phosphorylation domain of p120 catenin controls E-cadherin dynamics at the plasma membrane

Fukumoto

Shintani

Reynolds

et al. 2008

Experimental Cell Research

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In contrast to growth factor-stimulated tyrosine phosphorylation of p120, its relatively constitutive serine/threonine phosphorylation is not well understood. Here we examined the role of serine/ threonine phosphorylation of p120 in cadherin function. Expression of cadherins in cadherin-null cells converted them to an epithelial phenotype, induced p120 phosphorylation and localized it to sites of cell contact. Detergent solubility and immunofluorescence confirmed that phosphorylated p120 was at the plasma membrane. E-cadherin constructs incapable of traveling to the plasma membrane did not induce serine/threonine phosphorylation of p120, nor did cadherins constructs incapable of binding p120. However, an E-cadherin cytoplasmic domain construct artificially targeted to the plasma membrane did induce serine/threonine phosphorylation of p120, suggesting phosphorylation occurs independently of signals from cadherin dimerization and trafficking through the ER/Golgi. Solubility assays following calcium switch showed that p120 isoform 3A was more effective at stabilizing E-cadherin at the plasma membrane relative to isoform 4A. Since the major phosphorylation domain of p120 is included in isoform 3A but not 4A, we tested p120 mutated in the known phosphorylation sites in this domain, and found that it was even less effective at stabilizing E-cadherin. These data suggest that serine/threonine phosphorylation of p120 influences the dynamics of E-cadherin in junctions.

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CK1ε and p120‐catenin control Ror2 function in noncanonical Wnt signaling

et al. 2018

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Canonical and noncanonical Wnt pathways share some common elements but differ in the responses they evoke. Similar to Wnt ligands acting through the canonical pathway, Wnts that activate the noncanonical signaling, such as Wnt5a, promote Disheveled (Dvl) phosphorylation and its binding to the Frizzled (Fz) Wnt receptor complex. The protein kinase CK1ε is required for Dvl/Fz association in both canonical and noncanonical signaling. Here we show that differently to its binding to canonical Wnt receptor complex, CK1ε does not require p120‐catenin for the association with the Wnt5a co‐receptor Ror2. Wnt5a promotes the formation of the Ror2–Fz complex and enables the activation of Ror2‐bound CK1ε by Fz‐associated protein phosphatase 2A. Moreover, CK1ε also regulates Ror2 protein levels; CK1ε association stabilizes Ror2, which undergoes lysosomal‐dependent degradation in the absence of this kinase. Although p120‐catenin is not required for CK1ε association with Ror2, it also participates in this signaling pathway as p120‐catenin binds and maintains Ror2 at the plasma membrane; in p120‐depleted cells, Ror2 is rapidly internalized through a clathrin‐dependent mechanism. Accordingly, downregulation of p120‐catenin or CK1ε affects late responses to Wnt5a that are also sensitive to Ror2, such as SIAH2 transcription, cell invasion, or cortical actin polarization. Our results explain how CK1ε is activated by noncanonical Wnt and identify p120‐catenin and CK1ε as two critical factors controlling Ror2 function.

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A core function for p120-catenin in cadherin turnover

Cited by 663 publications

References 45 publications

The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

The regulatory or phosphorylation domain of p120 catenin controls E-cadherin dynamics at the plasma membrane

CK1ε and p120‐catenin control Ror2 function in noncanonical Wnt signaling

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