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Signal integration in TGF-β, WNT, and Hippo pathways.

Attisano L, Wrana JL - F1000Prime Rep (2013)

Bottom Line: Complete sequences of animal genomes have revealed a remarkably small and conserved toolbox of signalling pathways, such as TGF-β and WNT that account for all biological diversity.Intertwining of pathways is thus emerging as a key feature of a large, integrated and coordinated signalling network that allows cells to read a limited set of extrinsic cues, but mount the diverse responses that underpin successful development and homeostasis.Moreover, this design principle confounds the development of effective therapeutic interventions in complex diseases, such as cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Donnelly CCBR, University of Toronto 160 College Street, Toronto, ON Canada, M5S 3E1.

ABSTRACT
Complete sequences of animal genomes have revealed a remarkably small and conserved toolbox of signalling pathways, such as TGF-β and WNT that account for all biological diversity. This raises the question as to how such a limited set of cues elaborates so many diverse cell fates and behaviours. It is now clear that components of signalling pathways are physically assembled into higher order networks that ultimately dictate the biological output of pathway activity. Intertwining of pathways is thus emerging as a key feature of a large, integrated and coordinated signalling network that allows cells to read a limited set of extrinsic cues, but mount the diverse responses that underpin successful development and homeostasis. Moreover, this design principle confounds the development of effective therapeutic interventions in complex diseases, such as cancer.

No MeSH data available.


Related in: MedlinePlus

Integration of Cell Signalling Pathways into Higher Order Networks Sculpts Transcriptional LandscapesA simplified schematic of Hippo, TGF-β and WNT pathway interactions is shown. Each of the indicated pathways converge on transcriptional modulators that act in the nucleus to regulate transcription of target genes by interacting with DNA-binding partners, a selection of which are indicated (lowest cluster). Extensive physical interactions between Smads, β-catenin and TAZ/YAP (nuclear halo of components) describe a network of extensive crosstalk that provides for contextual transcriptional responses. In the presence of Hippo pathway activity, TAZ/YAP are sequestered in the cytosol, where they limit both TGF-β and WNT-β-catenin activity.
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fig-001: Integration of Cell Signalling Pathways into Higher Order Networks Sculpts Transcriptional LandscapesA simplified schematic of Hippo, TGF-β and WNT pathway interactions is shown. Each of the indicated pathways converge on transcriptional modulators that act in the nucleus to regulate transcription of target genes by interacting with DNA-binding partners, a selection of which are indicated (lowest cluster). Extensive physical interactions between Smads, β-catenin and TAZ/YAP (nuclear halo of components) describe a network of extensive crosstalk that provides for contextual transcriptional responses. In the presence of Hippo pathway activity, TAZ/YAP are sequestered in the cytosol, where they limit both TGF-β and WNT-β-catenin activity.

Mentions: In order to properly form tissues and organs, cells must not only integrate morphogenic signals provided by TGF-β, WNTs and other factors but also must incorporate information on the status of control pathways that govern overall cell and tissue growth. The Hippo pathway, initially identified in Drosophila, but well conserved in mammals, is one such pathway that acts as a major regulator of tissue growth and organ size [48-54]. Activation of the Hippo pathway, such as through cell-cell contact or upon polarization of epithelial cells, activates a cascade comprising the core kinases MST1/2 (encoded by the STK3 and STK4 genes) and LATS1/2 (Large tumor suppressor, homolog 1/2) that leads to phosphorylation of the related proteins TAZ (transcriptional co-activator with PDZ-binding motif) and YAP (Yes-associated protein), resulting in their cytoplasmic retention. In the absence of Hippo signalling, TAZ/YAP accumulate in the nucleus and in complex with various DNA binding factors, including TEADs (TEA domain family members) and Runx2 (runt related transcription factor 2), amongst others, that promote transcription of numerous target genes. Thus, unlike the TGF-β and WNT pathways that promote the nuclear activity of their respective mediators, Smads and β-catenin, activation of the Hippo pathway serves to turn off the nuclear functions of TAZ/YAP (see Figure 1). However, similar to the TGF-β and WNT pathways, a key transcriptional role for TAZ/YAP, primarily in cooperation with TEADs, in regulating stem and progenitor cell maintenance and differentiation has emerged [55-66].


Signal integration in TGF-β, WNT, and Hippo pathways.

Attisano L, Wrana JL - F1000Prime Rep (2013)

Integration of Cell Signalling Pathways into Higher Order Networks Sculpts Transcriptional LandscapesA simplified schematic of Hippo, TGF-β and WNT pathway interactions is shown. Each of the indicated pathways converge on transcriptional modulators that act in the nucleus to regulate transcription of target genes by interacting with DNA-binding partners, a selection of which are indicated (lowest cluster). Extensive physical interactions between Smads, β-catenin and TAZ/YAP (nuclear halo of components) describe a network of extensive crosstalk that provides for contextual transcriptional responses. In the presence of Hippo pathway activity, TAZ/YAP are sequestered in the cytosol, where they limit both TGF-β and WNT-β-catenin activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672943&req=5

fig-001: Integration of Cell Signalling Pathways into Higher Order Networks Sculpts Transcriptional LandscapesA simplified schematic of Hippo, TGF-β and WNT pathway interactions is shown. Each of the indicated pathways converge on transcriptional modulators that act in the nucleus to regulate transcription of target genes by interacting with DNA-binding partners, a selection of which are indicated (lowest cluster). Extensive physical interactions between Smads, β-catenin and TAZ/YAP (nuclear halo of components) describe a network of extensive crosstalk that provides for contextual transcriptional responses. In the presence of Hippo pathway activity, TAZ/YAP are sequestered in the cytosol, where they limit both TGF-β and WNT-β-catenin activity.
Mentions: In order to properly form tissues and organs, cells must not only integrate morphogenic signals provided by TGF-β, WNTs and other factors but also must incorporate information on the status of control pathways that govern overall cell and tissue growth. The Hippo pathway, initially identified in Drosophila, but well conserved in mammals, is one such pathway that acts as a major regulator of tissue growth and organ size [48-54]. Activation of the Hippo pathway, such as through cell-cell contact or upon polarization of epithelial cells, activates a cascade comprising the core kinases MST1/2 (encoded by the STK3 and STK4 genes) and LATS1/2 (Large tumor suppressor, homolog 1/2) that leads to phosphorylation of the related proteins TAZ (transcriptional co-activator with PDZ-binding motif) and YAP (Yes-associated protein), resulting in their cytoplasmic retention. In the absence of Hippo signalling, TAZ/YAP accumulate in the nucleus and in complex with various DNA binding factors, including TEADs (TEA domain family members) and Runx2 (runt related transcription factor 2), amongst others, that promote transcription of numerous target genes. Thus, unlike the TGF-β and WNT pathways that promote the nuclear activity of their respective mediators, Smads and β-catenin, activation of the Hippo pathway serves to turn off the nuclear functions of TAZ/YAP (see Figure 1). However, similar to the TGF-β and WNT pathways, a key transcriptional role for TAZ/YAP, primarily in cooperation with TEADs, in regulating stem and progenitor cell maintenance and differentiation has emerged [55-66].

Bottom Line: Complete sequences of animal genomes have revealed a remarkably small and conserved toolbox of signalling pathways, such as TGF-β and WNT that account for all biological diversity.Intertwining of pathways is thus emerging as a key feature of a large, integrated and coordinated signalling network that allows cells to read a limited set of extrinsic cues, but mount the diverse responses that underpin successful development and homeostasis.Moreover, this design principle confounds the development of effective therapeutic interventions in complex diseases, such as cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Donnelly CCBR, University of Toronto 160 College Street, Toronto, ON Canada, M5S 3E1.

ABSTRACT
Complete sequences of animal genomes have revealed a remarkably small and conserved toolbox of signalling pathways, such as TGF-β and WNT that account for all biological diversity. This raises the question as to how such a limited set of cues elaborates so many diverse cell fates and behaviours. It is now clear that components of signalling pathways are physically assembled into higher order networks that ultimately dictate the biological output of pathway activity. Intertwining of pathways is thus emerging as a key feature of a large, integrated and coordinated signalling network that allows cells to read a limited set of extrinsic cues, but mount the diverse responses that underpin successful development and homeostasis. Moreover, this design principle confounds the development of effective therapeutic interventions in complex diseases, such as cancer.

No MeSH data available.


Related in: MedlinePlus