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Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways

View Article: PubMed Central - PubMed

ABSTRACT

Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner.

No MeSH data available.


A schematic diagram showing parafibromin-mediated signal coordination.Signal inputs and outputs of the Wnt, Hh and Notch signals are coordinated intracellularly by parafibromin, which acts as a transcriptional platform/scaffold. Depending on its cellular context, parafibromin competitively interacts with β-catenin or Gli1, thereby activating Wnt and Hh signals in a mutually exclusive manner. On the other hand, parafibromin forms a heterotrimeric complex with β-catenin and Notch intracellular domain (NICD), supporting concerted activation of Wnt and Notch signals. This platform function of parafibromin is inversely regulated by parafibromin tyrosine phosphorylation and dephosphorylation, which are mediated by PTK6 and SHP2, respectively.
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f8: A schematic diagram showing parafibromin-mediated signal coordination.Signal inputs and outputs of the Wnt, Hh and Notch signals are coordinated intracellularly by parafibromin, which acts as a transcriptional platform/scaffold. Depending on its cellular context, parafibromin competitively interacts with β-catenin or Gli1, thereby activating Wnt and Hh signals in a mutually exclusive manner. On the other hand, parafibromin forms a heterotrimeric complex with β-catenin and Notch intracellular domain (NICD), supporting concerted activation of Wnt and Notch signals. This platform function of parafibromin is inversely regulated by parafibromin tyrosine phosphorylation and dephosphorylation, which are mediated by PTK6 and SHP2, respectively.

Mentions: Morphogens such as Wnt, Hedgehog and Notch are protein ligands that are present as secreted or membrane-bound forms, and they create concentration gradients to provide positional cues for organ development and tissue homeostasis123. In many cases, the Wnt and Notch signalling pathways play important roles in cell fate decision-making of the stem/progenitor cell compartment35, whereas Hh signalling transmits information to progenitor cells required for proper differentiation in both development and homeostasis36. At a single-cell level, these morphogen signals activate parallel information-processing conduits that converge onto the transcriptional effectors, which govern expression of genes specific to each morphogen. An important question here is how signals independently triggered by distinct morphogens are integrated and shaped intracellularly so that they can generate appropriate cellular responses in a spatiotemporally regulated manner. The present study revealed that, in addition to ligand production/receptor expression and cross-regulation/cross-talk at the levels of cytoplasmic signal transducers, a cellular response to these morphogens is determined by a combination of signal effectors aligned on parafibromin, which acts as a nuclear platform that integrates multiple distinct morphogen signals and converts them to integrated transcriptional outputs (a schematic diagram is depicted in Fig. 8).


Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways
A schematic diagram showing parafibromin-mediated signal coordination.Signal inputs and outputs of the Wnt, Hh and Notch signals are coordinated intracellularly by parafibromin, which acts as a transcriptional platform/scaffold. Depending on its cellular context, parafibromin competitively interacts with β-catenin or Gli1, thereby activating Wnt and Hh signals in a mutually exclusive manner. On the other hand, parafibromin forms a heterotrimeric complex with β-catenin and Notch intracellular domain (NICD), supporting concerted activation of Wnt and Notch signals. This platform function of parafibromin is inversely regulated by parafibromin tyrosine phosphorylation and dephosphorylation, which are mediated by PTK6 and SHP2, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5036006&req=5

f8: A schematic diagram showing parafibromin-mediated signal coordination.Signal inputs and outputs of the Wnt, Hh and Notch signals are coordinated intracellularly by parafibromin, which acts as a transcriptional platform/scaffold. Depending on its cellular context, parafibromin competitively interacts with β-catenin or Gli1, thereby activating Wnt and Hh signals in a mutually exclusive manner. On the other hand, parafibromin forms a heterotrimeric complex with β-catenin and Notch intracellular domain (NICD), supporting concerted activation of Wnt and Notch signals. This platform function of parafibromin is inversely regulated by parafibromin tyrosine phosphorylation and dephosphorylation, which are mediated by PTK6 and SHP2, respectively.
Mentions: Morphogens such as Wnt, Hedgehog and Notch are protein ligands that are present as secreted or membrane-bound forms, and they create concentration gradients to provide positional cues for organ development and tissue homeostasis123. In many cases, the Wnt and Notch signalling pathways play important roles in cell fate decision-making of the stem/progenitor cell compartment35, whereas Hh signalling transmits information to progenitor cells required for proper differentiation in both development and homeostasis36. At a single-cell level, these morphogen signals activate parallel information-processing conduits that converge onto the transcriptional effectors, which govern expression of genes specific to each morphogen. An important question here is how signals independently triggered by distinct morphogens are integrated and shaped intracellularly so that they can generate appropriate cellular responses in a spatiotemporally regulated manner. The present study revealed that, in addition to ligand production/receptor expression and cross-regulation/cross-talk at the levels of cytoplasmic signal transducers, a cellular response to these morphogens is determined by a combination of signal effectors aligned on parafibromin, which acts as a nuclear platform that integrates multiple distinct morphogen signals and converts them to integrated transcriptional outputs (a schematic diagram is depicted in Fig. 8).

View Article: PubMed Central - PubMed

ABSTRACT

Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner.

No MeSH data available.