Type Iγ phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with μ1B adaptin

Ling, Kun; Bairstow, Shawn F.; Carbonara, Chateen; Turbin, Dmitry; Huntsman, David G.; Anderson, Richard A.

doi:10.1083/jcb.200606023

Cited by 153 publications

(241 citation statements)

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“…Indeed, it was already described by other group that the V832M mutant, besides being present at the PM as described by our group, 15 is also largely accumulated in the cytosolic compartment. 28 Our results suggest that E-cadherin structural alterations decrease the affinity of exocytic partners to bind to E-cadherin molecules. We have previously shown that a great fraction of E-cadherin mutant protein is recognized as unfolded and is degraded by the endoplasmic reticulum quality control.…”

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 63%

“…[23][24][25][26] The association of b-catenin and PIPKIg to E-cadherin cytoplasmic tail is necessary for newly synthesized E-cadherin delivery to basal-lateral membrane. 27,28 At the PM, E-cadherin molecules constitutively undergo endocytosis and can either be recycled back to the PM or be degraded. 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.…”

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 99%

“…Interestingly, the mutants E757K, E781D and P799R seem to have a more deleterious effect than the mutant V832M, which is located within the PIPKIg binding region and was described to interfere with this interaction. 28 To understand whether a decreased interaction of E-cadherin with p120, b-catenin and PIPKIg, and an increased interaction with Hakai could reflect deficient E-cadherin surface expression and abnormal localization, we analyzed both parameters. We have found that other mutations, in addition to R749W and E757K, 21 can affect E-cadherin localization and surface expression.…”

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 99%

“…Newly synthesized E-cadherin is transported from the Golgi apparatus to the plasma membrane (PM), after the association of b-catenin and Type Ig phosphatidylinositol phosphate kinase (PIPKIg) to the cytoplasmic tail of E-cadherin. 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.…”

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: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

confidence: 63%

Section: Cdh1 Missense Mutations Affect E-cadherin Subcellular Localimentioning

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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“…Studies in Drosophila have also shown a requirement for Cdc42, the Par6/aPKC polarity pathway and ARP2/3 to maintain normal rates of E-cadherin internalization [107]. An interaction between E-cadherin and the type Ic phosphatidylinositol phosphate kinase isoform 2 splice variant (PIPK1ci2), which links E-cadherin to the clathrin adaptor protein complex AP-1B, seems to play a role in E-cadherin endocytosis and recycling [108] as well. Internalized E-cadherin can principally be targeted for lysosomal degradation or enter the recycling pathway for redelivery to the plasma membrane.…”

Section: Trafficking Of Other Cell Surface Adhesions Proteinsmentioning

confidence: 99%

On the move: endocytic trafficking in cell migration

Maritzen

Schachtner

Legler

2015

Cell. Mol. Life Sci.

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Directed cell migration is a fundamental process underlying diverse physiological and pathophysiological phenomena ranging from wound healing and induction of immune responses to cancer metastasis. Recent advances reveal that endocytic trafficking contributes to cell migration in multiple ways. (1) At the level of chemokines and chemokine receptors: internalization of chemokines by scavenger receptors is essential for shaping chemotactic gradients in tissue, whereas endocytosis of chemokine receptors and their subsequent recycling is key for maintaining a high responsiveness of migrating cells. (2) At the level of integrin trafficking and focal adhesion dynamics: endosomal pathways do not only modulate adhesion by delivering integrins to their site of action, but also by supplying factors for focal adhesion disassembly. (3) At the level of extracellular matrix reorganization: endosomal transport contributes to tumor cell migration not only by targeting integrins to invadosomes but also by delivering membrane type 1 matrix metalloprotease to the leading edge facilitating proteolysis-dependent chemotaxis. Consequently, numerous endocytic and endosomal factors have been shown to modulate cell migration. In fact key modulators of endocytic trafficking turn out to be also key regulators of cell migration. This review will highlight the recent progress in unraveling the contribution of cellular trafficking pathways to cell migration.

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Cadherin Trafficking and Junction Dynamics

Chiasson

Kowalczyk

2008

Cell Junctions

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Type Iγ phosphatidylinositol phosphate kinase modulates adherens junction and E-cadherin trafficking via a direct interaction with μ1B adaptin

Cited by 153 publications

References 58 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

On the move: endocytic trafficking in cell migration

Cadherin Trafficking and Junction Dynamics

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