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The importance of E...
The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC
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Figueiredo, Joana (författare)
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- Söderberg, Ola (författare)
- Uppsala universitet,Molekylära verktyg
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Simoes-Correia, Joana (författare)
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- Grannas, Karin (författare)
- Uppsala universitet,Molekylära verktyg
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Suriano, Gianpaolo (författare)
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Seruca, Raquel (författare)
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(creator_code:org_t)
- 2012-08-01
- 2013
- Engelska.
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:3, s. 301-309
- Relaterad länk:
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https://www.nature.c...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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, beta-catenin, PIPKI gamma 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.
Nyckelord
- HDGC
- E-cadherin
- CDH1 mutations
- E-cadherin trafficking
- E-cadherin binding partners
- diagnostic method
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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