Limits...
Terminating Wnt signals: a novel nuclear export mechanism targets activated (beta)-catenin.

Thorne ME, Gottardi CJ - J. Cell Biol. (2005)

Bottom Line: Nuclear targeting of beta-catenin is an obligatory step in Wnt signal transduction, but the factors that control import and export remain to be clarified.In this issue, Hendriksen et al. (p. 785) show that the RanBP3 export factor antagonizes beta-catenin/T cell factor (TCF) transcription by targeting the signaling-competent form of beta-catenin.We speculate that cells may use multiple export mechanisms to inhibit beta-catenin signaling in different ways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Northwestern University, Chicago, IL 60637, USA.

ABSTRACT
Nuclear targeting of beta-catenin is an obligatory step in Wnt signal transduction, but the factors that control import and export remain to be clarified. In this issue, Hendriksen et al. (p. 785) show that the RanBP3 export factor antagonizes beta-catenin/T cell factor (TCF) transcription by targeting the signaling-competent form of beta-catenin. We speculate that cells may use multiple export mechanisms to inhibit beta-catenin signaling in different ways.

Show MeSH
RanBP3 promotes export of activated β-catenin. During Wnt signaling, the Axin–GSK3β–APC phosphorylation/predestruction complex is inactivated and leads to cytosolic accumulation of a form of β-catenin that is unphosphorylated at GSK3β-dependent serines 37 and 41. This “activated” form is then available to enter the nucleus and participate as a coactivator for the transcription of TCF target genes. Data presented by Hendriksen et al. (2005) supports a model in which this activated form of β-catenin is exported from the nucleus by RanBP3 in a RanGTP-dependent manner. Cytosolic Ran GTPase-activating proteins promote GTP hydrolysis and presumably release the active form of β-catenin in the cytosol.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2171287&req=5

fig1: RanBP3 promotes export of activated β-catenin. During Wnt signaling, the Axin–GSK3β–APC phosphorylation/predestruction complex is inactivated and leads to cytosolic accumulation of a form of β-catenin that is unphosphorylated at GSK3β-dependent serines 37 and 41. This “activated” form is then available to enter the nucleus and participate as a coactivator for the transcription of TCF target genes. Data presented by Hendriksen et al. (2005) supports a model in which this activated form of β-catenin is exported from the nucleus by RanBP3 in a RanGTP-dependent manner. Cytosolic Ran GTPase-activating proteins promote GTP hydrolysis and presumably release the active form of β-catenin in the cytosol.

Mentions: In this issue, Hendriksen et al. (2005) set out to identify these elusive regulators of β-catenin import and export. Affinity chromatography was used to uncover proteins from Xenopus laevis extracts that interact with β-catenin. Two phenylalanine-glycine repeat–containing proteins were identified as the RanBP3 isoforms a and b. The Ran binding protein 3 (RanBP3) was originally identified as an exportin chromosome region maintenance 1 (CRM1)–dependent export factor, where it binds directly to the nuclear exporting receptor CRM1 and stimulates the export of CRM1 substrates that contain a leucine-rich nuclear export signal (Englmeier et al., 2001). Distinct from this mechanism, however, RanBP3's effects on β-catenin appear to be independent of CRM1. In this regard, RanBP3 b, and to a lesser extent RanBP3 a, was shown to bind directly to its β-catenin substrate (rather than indirectly through CRM1). Moreover, this interaction was enhanced by Ran-GTP, whereas a mutant form of RanBP3 unable to bind RanGTP exhibited reduced affinity for β-catenin, consistent with RanBP3 export function being coupled to a cycle of RanGTP binding and hydrolysis (Fig. 1). Overexpression and loss-of-function (small interfering RNA) approaches demonstrate that RanBP3 is a negative regulator of β-catenin signaling in human cell lines and in X. laevis and Drosophila melanogaster embryos. Thus, the mechanism by which RanBP3 inhibits β-catenin signaling has remained highly conserved throughout evolution.


Terminating Wnt signals: a novel nuclear export mechanism targets activated (beta)-catenin.

Thorne ME, Gottardi CJ - J. Cell Biol. (2005)

RanBP3 promotes export of activated β-catenin. During Wnt signaling, the Axin–GSK3β–APC phosphorylation/predestruction complex is inactivated and leads to cytosolic accumulation of a form of β-catenin that is unphosphorylated at GSK3β-dependent serines 37 and 41. This “activated” form is then available to enter the nucleus and participate as a coactivator for the transcription of TCF target genes. Data presented by Hendriksen et al. (2005) supports a model in which this activated form of β-catenin is exported from the nucleus by RanBP3 in a RanGTP-dependent manner. Cytosolic Ran GTPase-activating proteins promote GTP hydrolysis and presumably release the active form of β-catenin in the cytosol.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171287&req=5

fig1: RanBP3 promotes export of activated β-catenin. During Wnt signaling, the Axin–GSK3β–APC phosphorylation/predestruction complex is inactivated and leads to cytosolic accumulation of a form of β-catenin that is unphosphorylated at GSK3β-dependent serines 37 and 41. This “activated” form is then available to enter the nucleus and participate as a coactivator for the transcription of TCF target genes. Data presented by Hendriksen et al. (2005) supports a model in which this activated form of β-catenin is exported from the nucleus by RanBP3 in a RanGTP-dependent manner. Cytosolic Ran GTPase-activating proteins promote GTP hydrolysis and presumably release the active form of β-catenin in the cytosol.
Mentions: In this issue, Hendriksen et al. (2005) set out to identify these elusive regulators of β-catenin import and export. Affinity chromatography was used to uncover proteins from Xenopus laevis extracts that interact with β-catenin. Two phenylalanine-glycine repeat–containing proteins were identified as the RanBP3 isoforms a and b. The Ran binding protein 3 (RanBP3) was originally identified as an exportin chromosome region maintenance 1 (CRM1)–dependent export factor, where it binds directly to the nuclear exporting receptor CRM1 and stimulates the export of CRM1 substrates that contain a leucine-rich nuclear export signal (Englmeier et al., 2001). Distinct from this mechanism, however, RanBP3's effects on β-catenin appear to be independent of CRM1. In this regard, RanBP3 b, and to a lesser extent RanBP3 a, was shown to bind directly to its β-catenin substrate (rather than indirectly through CRM1). Moreover, this interaction was enhanced by Ran-GTP, whereas a mutant form of RanBP3 unable to bind RanGTP exhibited reduced affinity for β-catenin, consistent with RanBP3 export function being coupled to a cycle of RanGTP binding and hydrolysis (Fig. 1). Overexpression and loss-of-function (small interfering RNA) approaches demonstrate that RanBP3 is a negative regulator of β-catenin signaling in human cell lines and in X. laevis and Drosophila melanogaster embryos. Thus, the mechanism by which RanBP3 inhibits β-catenin signaling has remained highly conserved throughout evolution.

Bottom Line: Nuclear targeting of beta-catenin is an obligatory step in Wnt signal transduction, but the factors that control import and export remain to be clarified.In this issue, Hendriksen et al. (p. 785) show that the RanBP3 export factor antagonizes beta-catenin/T cell factor (TCF) transcription by targeting the signaling-competent form of beta-catenin.We speculate that cells may use multiple export mechanisms to inhibit beta-catenin signaling in different ways.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Northwestern University, Chicago, IL 60637, USA.

ABSTRACT
Nuclear targeting of beta-catenin is an obligatory step in Wnt signal transduction, but the factors that control import and export remain to be clarified. In this issue, Hendriksen et al. (p. 785) show that the RanBP3 export factor antagonizes beta-catenin/T cell factor (TCF) transcription by targeting the signaling-competent form of beta-catenin. We speculate that cells may use multiple export mechanisms to inhibit beta-catenin signaling in different ways.

Show MeSH