Spelling suggestions: "subject:"glypican3"" "subject:"glypican""
1 |
Élucidation et identification des différents interacteurs impliqués dans le mécanisme de régulation du LDLR par la protéine PCSK9 / Identifying and decoding the role of different protein interactors involve in the LDLR degradation mediated by PCSK9Ly, Kévin January 2016 (has links)
Résumé : Les maladies cardiovasculaires représentent la principale cause de mortalité mondiale, soit le tiers des décès annuels selon l’Organisation mondiale de la Santé. L’hypercholestérolémie, caractérisée par une élévation des niveaux plasmatiques de lipoprotéines de faible densité (LDL), est l’un des facteurs de risque majeur pour les maladies cardiovasculaires. La proprotéine convertase subtilisine/kexine type 9 (PCSK9) joue un rôle essentiel dans l’homéostasie du cholestérol sanguin par la régulation des niveaux protéiques du récepteur LDL (LDLR). PCSK9 est capable de se lier au LDLR et favorise l’internalisation et la dégradation du récepteur dans les lysosomes. L’inhibition de PCSK9 s’avère une cible thérapeutique validée pour le traitement de l’hypercholestérolémie et la prévention des maladies cardiovasculaires. Par contre, plusieurs mécanismes responsables de la régulation et la dégradation du complexe PCSK9-LDLR n’ont pas encore été complètement caractérisés comme la régulation par la protéine annexin A2 (AnxA2), un inhibiteur endogène de PCSK9. De plus, plusieurs évidences suggèrent la présence d’une ou plusieurs protéines, encore inconnues, impliquées dans le mécanisme d’action de PCSK9. Celles-ci pourraient réguler l’internalisation et le transport du complexe PCSK9-LDLR vers les lysosomes. Les objectifs de cette thèse sont de mieux définir le rôle et l’impact de l’AnxA2 sur la protéine PCSK9 en plus d’identifier de nouveaux partenaires d’interactions de PCSK9 pour mieux caractériser son mécanisme d’action sur la régulation des niveaux de LDLR. Nous avons démontré que l’inhibition de PCSK9 par l’AnxA2 extracellulaire s’effectue via sa liaison aux domaines M1+M2 de la région C-terminale de PCSK9 et nous avons mis en évidence les premières preuves d’un contrôle intracellulaire de l’AnxA2 sur la traduction de l’ARNm de PCSK9. Nos résultats révèlent une liaison de l’AnxA2 à l’ARN messager de PCSK9 qui cause une répression traductionnelle. Nous avons également identifié la protéine glypican-3 (GPC3) comme un nouveau partenaire d’interaction extracellulaire avec le PCSK9 et intracellulaire avec le complexe PCSK9-LDLR dans le réticulum endoplasmique des cellules HepG2 et Huh7. Nos études démontrent que GPC3 réduit l’activité extracellulaire de PCSK9 en agissant comme un compétiteur du LDLR pour la liaison avec PCSK9. Une meilleure compréhension des mécanismes de régulation et de dégradation du complexe PCKS9-LDLR permettra de mieux évaluer l’impact et l’efficacité des inhibiteurs de la protéine PCSK9. / Abstract : Cardiovascular disease is the leading cause of global mortality, responsible for one third of global deaths, according to the latest statistics from World Health Organization. Hypercholesterolemia, characterized by increased plasma low-density lipoprotein (LDL) cholesterol, is a major determinant of cardiovascular disease risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in cholesterol homeostasis by regulating LDL receptor (LDLR) protein levels. PCSK9 binds to the LDLR and promotes its internalization and degradation in late endosomal/lysosomal compartments. Inhibition of PCSK9 action on LDLR has emerged as a novel therapeutic target for hypercholesterolemia and the prevention of cardiovascular disease. Annexin A2 (AnxA2) was reported as an endogenous extracellular inhibitor of PCSK9 activity upon cell-surface LDLR degradation and mechanisms of PCSK9’s regulation by AnxA2. However, its role on PCSK9 regulation still need better characterization in hepatocellular carcinoma cell lines. Moreover, many evidences suggest the presence of additional unknown interaction partners involve in the LDLR regulation and degradation mediated by PCSK9. These unknown partners could regulate the internalization and trafficking of the PCSK9-LDLR complex to lysosomes. The objectives of this thesis are to better define the role and impact of AnxA2 on PCSK9 and to identify novel PCSK9 interacting partners that participate and regulate the PCSK9-LDLR complex formation and degradation. We demonstrated that PCSK9 inhibition by extracellular AnxA2 occurs via its interaction with the M1+M2 modules of PCSK9’s C-terminal region. Most importantly, we revealed a new role of intracellular AnxA2 in the reduction of PCSK9 protein levels via a translational mechanism. Our results suggest a translational repression from the binding of AnxA2 to PCSK9’s mRNA. Also, we successfully identified a novel and functional interaction between glypican-3 (GPC3) and PCSK9. We demonstrated the extracellular GPC3 interaction with PCSK9 and the intracellular GPC3 with both PCSK9 and LDLR in human hepatocellular carcinoma cell lines HepG2 and Huh7. Our studies revealed that extracellular GPC3 can act as an endogenous competitive binding partner of PCSK9 to the LDLR, and hence reducing its activity towards LDLR degradation. The continued understanding of PCSK9 interactions is critical, from a mechanistic point of view as well as from the optimization of therapeutic interventions.
|
2 |
Glypican-3 Stimulates the WNT Signaling Pathway by Facilitating/Stabilizing the Interaction of WNT LIigand and Frizzled ReceptorMartin, Tonya 12 January 2011 (has links)
Glypican-3 (GPC3) belongs to a family of cell surface proteoglycans. GPC3 regulates the activity of several morphogens and growth factors that play critical roles during development. Disrupting the function of GPC3 leads to disease, including the overgrowth disease Simpson Golabi Behmel Syndrome (SGBS) and Cancer. Previous work has shown that GPC3 is over expressed in Hepatocellular Carcinoma (HCC), and that HCC proliferation is stimulated through GPC3 mediated activation of the Wnt signaling pathway. Glypicans are known to regulate Wnt signaling in a variety of model organisms including Drosophila and mouse.
This work investigates the hypothesis that GPC3 stimulates Wnt signaling by facilitating/stabilizing the interaction between Wnt and its receptor Frizzled (Fzd). Consistent with this hypothesis, we found that GPC3 is able to bind both Wnt and Fzd. The binding of GPC3 to Fzd is mediated by the GPC3 glycosaminoglycan chains and by the cysteine rich domain of Fzd.
|
3 |
Glypican-3 Stimulates the WNT Signaling Pathway by Facilitating/Stabilizing the Interaction of WNT LIigand and Frizzled ReceptorMartin, Tonya 12 January 2011 (has links)
Glypican-3 (GPC3) belongs to a family of cell surface proteoglycans. GPC3 regulates the activity of several morphogens and growth factors that play critical roles during development. Disrupting the function of GPC3 leads to disease, including the overgrowth disease Simpson Golabi Behmel Syndrome (SGBS) and Cancer. Previous work has shown that GPC3 is over expressed in Hepatocellular Carcinoma (HCC), and that HCC proliferation is stimulated through GPC3 mediated activation of the Wnt signaling pathway. Glypicans are known to regulate Wnt signaling in a variety of model organisms including Drosophila and mouse.
This work investigates the hypothesis that GPC3 stimulates Wnt signaling by facilitating/stabilizing the interaction between Wnt and its receptor Frizzled (Fzd). Consistent with this hypothesis, we found that GPC3 is able to bind both Wnt and Fzd. The binding of GPC3 to Fzd is mediated by the GPC3 glycosaminoglycan chains and by the cysteine rich domain of Fzd.
|
Page generated in 0.0422 seconds