Your browser doesn't support javascript.
loading
Montrer: 20 | 50 | 100
Résultats 1 - 5 de 5
Filtrer
Plus de filtres











Base de données
Gamme d'année
1.
Life Sci Alliance ; 7(9)2024 Sep.
Article de Anglais | MEDLINE | ID: mdl-38969364

RÉSUMÉ

The transmembrane E3 ligases RNF43 and ZNRF3 perform key tumour suppressor roles by inducing endocytosis of members of the Frizzled (FZD) family, the primary receptors for WNT. Loss-of-function mutations in RNF43 and ZNRF3 mediate FZD stabilisation and a WNT-hypersensitive growth state in various cancer types. Strikingly, RNF43 and ZNRF3 mutations are differentially distributed across cancer types, raising questions about their functional redundancy. Here, we compare the efficacy of RNF43 and ZNRF3 of targeting different FZDs for endocytosis. We find that RNF43 preferentially down-regulates FZD1/FZD5/FZD7, whereas ZNRF3 displays a preference towards FZD6. We show that the RNF43 transmembrane domain (TMD) is a key molecular determinant for inducing FZD5 endocytosis. Furthermore, a TMD swap between RNF43 and ZNRF3 re-directs their preference for FZD5 down-regulation. We conclude that RNF43 and ZNRF3 preferentially down-regulate specific FZDs, in part by a TMD-dependent mechanism. In accordance, tissue-specific expression patterns of FZD homologues correlate with the incidence of RNF43 or ZNRF3 cancer mutations in those tissues. Consequently, our data point to druggable vulnerabilities of specific FZD receptors in RNF43- or ZNRF3-mutant human cancers.


Sujet(s)
Endocytose , Récepteurs Frizzled , Ubiquitin-protein ligases , Récepteurs Frizzled/métabolisme , Récepteurs Frizzled/génétique , Humains , Endocytose/génétique , Ubiquitin-protein ligases/métabolisme , Ubiquitin-protein ligases/génétique , Cellules HEK293 , Mutation , Voie de signalisation Wnt/génétique , Régulation négative/génétique
3.
Nat Rev Cancer ; 21(1): 5-21, 2021 01.
Article de Anglais | MEDLINE | ID: mdl-33097916

RÉSUMÉ

Mutation-induced activation of WNT-ß-catenin signalling is a frequent driver event in human cancer. Sustained WNT-ß-catenin pathway activation endows cancer cells with sustained self-renewing growth properties and is associated with therapy resistance. In healthy adult stem cells, WNT pathway activity is carefully controlled by core pathway tumour suppressors as well as negative feedback regulators. Gene inactivation experiments in mouse models unequivocally demonstrated the relevance of WNT tumour suppressor loss-of-function mutations for cancer growth. However, in human cancer, a far more complex picture has emerged in which missense or truncating mutations mediate stable expression of mutant proteins, with distinct functional and phenotypic ramifications. Herein, we review recent advances and challenges in our understanding of how different mutational subsets of WNT tumour suppressor genes link to distinct cancer types, clinical outcomes and treatment strategies.


Sujet(s)
Antinéoplasiques/usage thérapeutique , Thérapie moléculaire ciblée , Mutation , Tumeurs/traitement médicamenteux , Protéines suppresseurs de tumeurs/génétique , Protéines de type Wingless/génétique , Voie de signalisation Wnt/effets des médicaments et des substances chimiques , Animaux , Humains , Tumeurs/génétique , Tumeurs/anatomopathologie
4.
EMBO J ; 39(18): e103932, 2020 09 15.
Article de Anglais | MEDLINE | ID: mdl-32965059

RÉSUMÉ

Wnt/ß-catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt-hypersensitive tumors that are susceptible to anti-Wnt-based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce ß-catenin-mediated transcription, despite exhibiting retained Wnt receptor downregulation. These mutations interfere with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail that involves Casein kinase 1 (CK1) binding and phosphorylation. Mechanistically, truncated RNF43 variants trap CK1 at the plasma membrane, thereby preventing ß-catenin turnover and propelling ligand-independent target gene transcription. Gene editing of human colon stem cells shows that RNF43 truncations cooperate with p53 loss to drive a niche-independent program for self-renewal and proliferation. Moreover, these RNF43 variants confer decreased sensitivity to anti-Wnt-based therapy. Our data demonstrate the relevance of studying patient-derived mutations for understanding disease mechanisms and improved applications of precision medicine.


Sujet(s)
Casein kinase I/métabolisme , Tumeurs/métabolisme , Ubiquitin-protein ligases/métabolisme , Voie de signalisation Wnt , Casein kinase I/génétique , Cellules HEK293 , Humains , Tumeurs/génétique , Tumeurs/anatomopathologie , Protéine p53 suppresseur de tumeur/génétique , Protéine p53 suppresseur de tumeur/métabolisme , Ubiquitin-protein ligases/génétique , bêta-Caténine/génétique , bêta-Caténine/métabolisme
5.
Proc Natl Acad Sci U S A ; 115(17): E3996-E4005, 2018 04 24.
Article de Anglais | MEDLINE | ID: mdl-29632210

RÉSUMÉ

Wnt/ß-catenin signaling controls development and adult tissue homeostasis by regulating cell proliferation and cell fate decisions. Wnt binding to its receptors Frizzled (FZD) and low-density lipoprotein-related 6 (LRP6) at the cell surface initiates a signaling cascade that leads to the transcription of Wnt target genes. Upon Wnt binding, the receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The molecular basis of signalosome formation and regulation remains elusive, largely due to the lack of tools to analyze its endogenous components. Here, we use internally tagged Wnt3a proteins to isolate and characterize activated, endogenous Wnt receptor complexes by mass spectrometry-based proteomics. We identify the single-span membrane protein TMEM59 as an interactor of FZD and LRP6 and a positive regulator of Wnt signaling. Mechanistically, TMEM59 promotes the formation of multimeric Wnt-FZD assemblies via intramembrane interactions. Subsequently, these Wnt-FZD-TMEM59 clusters merge with LRP6 to form mature Wnt signalosomes. We conclude that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps that involve regulated intramembrane interactions.


Sujet(s)
Protéine-6 apparentée au récepteur des LDL/métabolisme , Protéines membranaires/métabolisme , Complexes multiprotéiques/métabolisme , Protéines de tissu nerveux/métabolisme , Voie de signalisation Wnt/physiologie , Protéine Wnt3A/métabolisme , Animaux , Cellules HEK293 , Humains , Protéine-6 apparentée au récepteur des LDL/génétique , Protéines membranaires/génétique , Souris , Complexes multiprotéiques/génétique , Protéines de tissu nerveux/génétique , Protéine Wnt3A/génétique
SÉLECTION CITATIONS
DÉTAIL DE RECHERCHE