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Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts.

Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, Chapman HA - J. Cell Biol. (2009)

Bottom Line: Injury-initiated epithelial to mesenchymal transition (EMT) depends on contextual signals from the extracellular matrix, suggesting a role for integrin signaling.A mechanism for this defect was explored in alpha3- cells reconstituted with wild-type (wt) alpha3 or point mutants unable to engage laminin 5 (G163A) or epithelial cadherin (E-cadherin; H245A).These findings demonstrate that alpha3beta1 coordinates cross talk between beta-catenin and Smad signaling pathways as a function of extracellular contact cues and thereby regulates responses to TGF-beta1 activation.

View Article: PubMed Central - PubMed

Affiliation: Pulmonary and Critical Care Division, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
Injury-initiated epithelial to mesenchymal transition (EMT) depends on contextual signals from the extracellular matrix, suggesting a role for integrin signaling. Primary epithelial cells deficient in their prominent laminin receptor, alpha3beta1, were found to have a markedly blunted EMT response to TGF-beta1. A mechanism for this defect was explored in alpha3- cells reconstituted with wild-type (wt) alpha3 or point mutants unable to engage laminin 5 (G163A) or epithelial cadherin (E-cadherin; H245A). After TGF-beta1 stimulation, wt epithelial cells but not cells expressing the H245A mutant internalize complexes of E-cadherin and TGF-beta1 receptors, generate phospho-Smad2 (p-Smad2)-pY654-beta-catenin complexes, and up-regulate mesenchymal target genes. Although Smad2 phosphorylation is normal, p-Smad2-pY654-beta-catenin complexes do not form in the absence of alpha3 or when alpha3beta1 is mainly engaged on laminin 5 or E-cadherin in adherens junctions, leading to attenuated EMT. These findings demonstrate that alpha3beta1 coordinates cross talk between beta-catenin and Smad signaling pathways as a function of extracellular contact cues and thereby regulates responses to TGF-beta1 activation.

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Model of TGF-β1 signaling. The schematic illustration summarizes the influence of α3β1 on TGF-β1 signaling as a function of cell–cell and cell–matrix contacts. For details see the Discussion.
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fig8: Model of TGF-β1 signaling. The schematic illustration summarizes the influence of α3β1 on TGF-β1 signaling as a function of cell–cell and cell–matrix contacts. For details see the Discussion.

Mentions: The findings reported in this study identify a previously unrecognized role for the prominent epithelial integrin α3β1 in TGF-β1 signaling, providing evidence that the integrin functions as a sensor of cell contacts to regulate TGF-β1 signaling. The essential function of α3β1 appears to depend on the presence of surface complexes on epithelial cells, which are comprised of a subfraction of the surface pool of α3β1, E-cadherin, and TGF-βR1, which critically influence the signaling response to TGF-β1. The components of this complex by itself reveals the likely elements of its function, as modeled in Fig. 8. Surface complexes of E-cadherin and TGF-βR1 bring two key transcription factors involved in induction of EMT into spatial proximity: β-catenin and receptor Smads (Chilosi et al., 2003; Kalluri and Neilson, 2003; Yook et al., 2006). After TGF-β1 stimulation, the surface complexes are internalized, and β-catenin is phosphorylated on Y-654. The formation of stable complexes between pY654–β-catenin and p-Smad2 and the appearance of these complexes strongly correlate with subsequent EMT-related protein expression (Figs. 5–7). Both internalization and β-catenin tyrosine phosphorylation require the third component of the complex, α3β1. The unique function of α3β1 in this context appears to reside in its affinity for E-cadherin, without which E-cadherin–TGF-βR1 complex internalization is impaired, and this signaling system does not operate. Conceptually, these findings are similar to prior evidence in another system in which integrin engagement is found to regulate growth factor signaling at least in part by altering pathways of endocytosis that influence the quality and duration of receptor signaling (del Pozo et al., 2004). However, our findings also reveal a completely new point of intersection between β-catenin and Smad signaling pathways (Lei et al., 2004), and the linkage of this point of intersection to a dynamic interplay between adhesion receptors and their normal pericellular contacts provides new understanding for how the extracellular environment can regulate the epithelial cell response to TGF-β1 (Masszi et al., 2004; Thiery and Sleeman, 2006).


Integrin alpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signaling to cell contacts.

Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, Chapman HA - J. Cell Biol. (2009)

Model of TGF-β1 signaling. The schematic illustration summarizes the influence of α3β1 on TGF-β1 signaling as a function of cell–cell and cell–matrix contacts. For details see the Discussion.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2654298&req=5

fig8: Model of TGF-β1 signaling. The schematic illustration summarizes the influence of α3β1 on TGF-β1 signaling as a function of cell–cell and cell–matrix contacts. For details see the Discussion.
Mentions: The findings reported in this study identify a previously unrecognized role for the prominent epithelial integrin α3β1 in TGF-β1 signaling, providing evidence that the integrin functions as a sensor of cell contacts to regulate TGF-β1 signaling. The essential function of α3β1 appears to depend on the presence of surface complexes on epithelial cells, which are comprised of a subfraction of the surface pool of α3β1, E-cadherin, and TGF-βR1, which critically influence the signaling response to TGF-β1. The components of this complex by itself reveals the likely elements of its function, as modeled in Fig. 8. Surface complexes of E-cadherin and TGF-βR1 bring two key transcription factors involved in induction of EMT into spatial proximity: β-catenin and receptor Smads (Chilosi et al., 2003; Kalluri and Neilson, 2003; Yook et al., 2006). After TGF-β1 stimulation, the surface complexes are internalized, and β-catenin is phosphorylated on Y-654. The formation of stable complexes between pY654–β-catenin and p-Smad2 and the appearance of these complexes strongly correlate with subsequent EMT-related protein expression (Figs. 5–7). Both internalization and β-catenin tyrosine phosphorylation require the third component of the complex, α3β1. The unique function of α3β1 in this context appears to reside in its affinity for E-cadherin, without which E-cadherin–TGF-βR1 complex internalization is impaired, and this signaling system does not operate. Conceptually, these findings are similar to prior evidence in another system in which integrin engagement is found to regulate growth factor signaling at least in part by altering pathways of endocytosis that influence the quality and duration of receptor signaling (del Pozo et al., 2004). However, our findings also reveal a completely new point of intersection between β-catenin and Smad signaling pathways (Lei et al., 2004), and the linkage of this point of intersection to a dynamic interplay between adhesion receptors and their normal pericellular contacts provides new understanding for how the extracellular environment can regulate the epithelial cell response to TGF-β1 (Masszi et al., 2004; Thiery and Sleeman, 2006).

Bottom Line: Injury-initiated epithelial to mesenchymal transition (EMT) depends on contextual signals from the extracellular matrix, suggesting a role for integrin signaling.A mechanism for this defect was explored in alpha3- cells reconstituted with wild-type (wt) alpha3 or point mutants unable to engage laminin 5 (G163A) or epithelial cadherin (E-cadherin; H245A).These findings demonstrate that alpha3beta1 coordinates cross talk between beta-catenin and Smad signaling pathways as a function of extracellular contact cues and thereby regulates responses to TGF-beta1 activation.

View Article: PubMed Central - PubMed

Affiliation: Pulmonary and Critical Care Division, Department of Medicine, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.

ABSTRACT
Injury-initiated epithelial to mesenchymal transition (EMT) depends on contextual signals from the extracellular matrix, suggesting a role for integrin signaling. Primary epithelial cells deficient in their prominent laminin receptor, alpha3beta1, were found to have a markedly blunted EMT response to TGF-beta1. A mechanism for this defect was explored in alpha3- cells reconstituted with wild-type (wt) alpha3 or point mutants unable to engage laminin 5 (G163A) or epithelial cadherin (E-cadherin; H245A). After TGF-beta1 stimulation, wt epithelial cells but not cells expressing the H245A mutant internalize complexes of E-cadherin and TGF-beta1 receptors, generate phospho-Smad2 (p-Smad2)-pY654-beta-catenin complexes, and up-regulate mesenchymal target genes. Although Smad2 phosphorylation is normal, p-Smad2-pY654-beta-catenin complexes do not form in the absence of alpha3 or when alpha3beta1 is mainly engaged on laminin 5 or E-cadherin in adherens junctions, leading to attenuated EMT. These findings demonstrate that alpha3beta1 coordinates cross talk between beta-catenin and Smad signaling pathways as a function of extracellular contact cues and thereby regulates responses to TGF-beta1 activation.

Show MeSH
Related in: MedlinePlus