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Activation of CK1? by PP2A/PR61? is required for the initiation of Wnt signaling.

ABSTRACT: Canonical Wnt signaling induces the stabilization of ?-catenin, its translocation to the nucleus and the activation of target promoters. This pathway is initiated by the binding of Wnt ligands to the Frizzled receptor, the association of the LRP5/6 co-receptor and the formation of a complex comprising Dvl-2, Axin and protein kinases CK1?, ?, ? and GSK3. Among these, activation of CK1?, constitutively bound to LRP5/6 through p120-catenin, is required for the association of the rest of the components. We describe here that CK1? is activated by the PP2A/PR61? phosphatase. Binding of Wnt ligands promotes the interaction of LRP5/6-associated CK1? with Frizzled-bound PR61? regulatory subunit, facilitating the access of PP2A catalytic subunit to CK1? and its activation, what enables the recruitment of Dvl-2 to the receptor complex and the initiation of the Wnt pathway. Our results uncover the mechanism of activation of the canonical Wnt pathway by its ligands.

SUBMITTER: Vinyoles M

PROVIDER: S-EPMC5173447 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling.

Vinyoles M M Del Valle-Pérez B B Curto J J Padilla M M Villarroel A A Yang J J de Herreros A G AG Duñach M M

Oncogene 20160620 3

Canonical Wnt signaling induces the stabilization of β-catenin, its translocation to the nucleus and the activation of target promoters. This pathway is initiated by the binding of Wnt ligands to the Frizzled receptor, the association of the LRP5/6 co-receptor and the formation of a complex comprising Dvl-2, Axin and protein kinases CK1α, ɛ, γ and GSK3. Among these, activation of CK1ɛ, constitutively bound to LRP5/6 through p120-catenin, is required for the association of the rest of the compone ...[more]

PMID: 27321178

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Project description:BACKGROUND: The high-mobility-group (HMG) proteins are the most abundant non-histone chromatin-associated proteins. HMG proteins are present at high levels in various undifferentiated tissues during embryonic development and their levels are strongly reduced in the corresponding adult tissues, where they have been implicated in maintaining and activating stem/progenitor cells. Here we deciphered the role of the high-mobility-group AT-hook protein 2 (HMGA2) during lung development by analyzing the lung of Hmga2-deficient mice (Hmga2(-/-)). RESULTS: We found that Hmga2 is expressed in the mouse embryonic lung at the distal airways. Analysis of Hmga2(-/-) mice showed that Hmga2 is required for proper cell proliferation and distal epithelium differentiation during embryonic lung development. Hmga2 knockout led to enhanced canonical WNT signaling due to an increased expression of secreted WNT glycoproteins Wnt2b, Wnt7b and Wnt11 as well as a reduction of the WNT signaling antagonizing proteins GATA-binding protein 6 and frizzled homolog 2. Analysis of siRNA-mediated loss-of-function experiments in embryonic lung explant culture confirmed the role of Hmga2 as a key regulator of distal lung epithelium differentiation and supported the causal involvement of enhanced canonical WNT signaling in mediating the effect of Hmga2-loss-of-fuction. Finally, we found that HMGA2 directly regulates Gata6 and thereby modulates Fzd2 expression. CONCLUSIONS: Our results support that Hmga2 regulates canonical WNT signaling at different points of the pathway. Increased expression of the secreted WNT glycoproteins might explain a paracrine effect by which Hmga2-knockout enhanced cell proliferation in the mesenchyme of the developing lung. In addition, HMGA2-mediated direct regulation of Gata6 is crucial for fine-tuning the activity of WNT signaling in the airway epithelium. Our results are the starting point for future studies investigating the relevance of Hmga2-mediated regulation of WNT signaling in the adult lung within the context of proper balance between differentiation and self-renewal of lung stem/progenitor cells during lung regeneration in both homeostatic turnover and repair after injury.

Dataset Information

Activation of CK1? by PP2A/PR61? is required for the initiation of Wnt signaling.

Publications

Activation of CK1ɛ by PP2A/PR61ɛ is required for the initiation of Wnt signaling.

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