Regulation of β‐Catenin Nuclear Dynamics by GSK‐3β Involves a LEF‐1 Positive Feedback Loop

Jamieson, Cara; Sharma, Manisha; Henderson, Beric R.

doi:10.1111/j.1600-0854.2011.01207.x

Cited by 50 publications

(51 citation statements)

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“…␤-Catenin transiently binds to the FG repeats of Nup358 (located at the cytoplasmic filaments), Nup62 (central channel of NPC), Nup98 and Nup153 (located at the nuclear basket of NPC). herins, respectively (24,36,38). Here, we have re-assessed the potential role of the Arm repeat domain to mediate active transport of ␤-catenin.…”

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confidence: 99%

Specific Armadillo Repeat Sequences Facilitate β-Catenin Nuclear Transport in Live Cells via Direct Binding to Nucleoporins Nup62, Nup153, and RanBP2/Nup358

Sharma

Jamieson

Johnson

et al. 2012

Journal of Biological Chemistry

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Background:The nuclear localization of ␤-catenin is directly linked to its cancer causing activity. Results: Armadillo repeats (10 -12) mediate nuclear transport of ␤-catenin through direct interaction with specific nuclear pore complex proteins. Conclusion: ␤-Catenin can function like a nuclear transport receptor in its ability to translocate independently through the nuclear pore complex. Significance: ␤-Catenin may transport specific binding partners between the nucleus and cytoplasm in response to Wnt signaling.␤-Catenin transduces the Wnt signal from the membrane to nucleus, and certain gene mutations trigger its nuclear accumulation leading to cell transformation and cancer. ␤-Catenin shuttles between the nucleus and cytoplasm independent of classical Ran/transport receptor pathways, and this movement was previously hypothesized to involve the central Armadillo (Arm) domain. Fluorescence recovery after photobleaching (FRAP) assays were used to delineate functional transport regions of the Arm domain in living cells. The strongest nuclear import/export activity was mapped to Arm repeats R10 -12 using both in vivo FRAP and in vitro export assays. By comparison, Arm repeats R3-8 of ␤-catenin were highly active for nuclear import but displayed a comparatively weak export activity. We show for the first time using purified components that specific Arm sequences of ␤-catenin interact directly in vitro with the FG repeats of the nuclear pore complex (NPC) components Nup62, Nup98, and Nup153, indicating an independent ability of ␤-catenin to traverse the NPC. Moreover, a proteomics screen identified RanBP2/Nup358 as a binding partner of Arm R10 -12, and ␤-catenin was confirmed to interact with endogenous and ectopic forms of Nup358. We further demonstrate that knock-down of endogenous Nup358 and Nup62 impeded the rate of nuclear import/export of ␤-catenin to a greater extent than that of importin-␤. The Arm R10 -12 sequence facilitated transport even when ␤-catenin was bound to the Arm-binding partner LEF-1, and its activity was stimulated by phosphorylation at Tyr-654. These findings provide functional evidence that the Arm domain contributes to regulated ␤-catenin transport through direct interaction with the NPC.The canonical Wnt signaling pathway regulates normal tissue development and maintenance through its effector molecule, ␤-catenin. In the absence of Wnt signaling ␤-catenin accumulates at adherens junctions. ␤-Catenin levels are regulated through degradation by a destruction complex, comprising of adenomatous polyposis coli (APC), 4 axin, casein kinase I, and glycogen synthase kinase-3␤, which phosphorylates and subsequently ubiquitinates ␤-catenin at the N terminus, leading to its degradation by the proteosome (1, 2). On receiving Wnt signals or through misregulation of the degradation pathway, ␤-catenin is stabilized and accumulates in the nucleus where it binds to lymphoid enhancer factor-1 (LEF/ TCF) transcription factors and activates transcription of tumor promoting genes involved in cell migration...

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Specific Armadillo Repeat Sequences Facilitate β-Catenin Nuclear Transport in Live Cells via Direct Binding to Nucleoporins Nup62, Nup153, and RanBP2/Nup358

Sharma

Jamieson

Johnson

et al. 2012

Journal of Biological Chemistry

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“…The influence from Wnt7a to DBZ is modeled using a Hill function, supported by the observation that there is the positive and reinforcing feedback loop from Lef-1 to Wnt7a (56). The Wnt-Notch cross-talk relationship was based on previous compartmental models (31).…”

Section: Methodsmentioning

confidence: 99%

Shaping organs by a wingless-int/Notch/nonmuscle myosin module which orients feather bud elongation

Chen

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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How organs are shaped to specific forms is a fundamental issue in developmental biology. To address this question, we used the repetitive, periodic pattern of feather morphogenesis on chicken skin as a model. Avian feathers within a single tract extend from dome-shaped primordia to thin conical structures with a common axis of orientation. From a systems biology perspective, the process is precise and robust. Using tissue transplantation assays, we demonstrate that a "zone of polarizing activity," localized in the posterior feather bud, is necessary and sufficient to mediate the directional elongation. This region contains a spatially well-defined nuclear β-catenin zone, which is induced by wingless-int (Wnt)7a protein diffusing in from posterior bud epithelium. Misexpressing nuclear β-catenin randomizes feather polarity. This dermal nuclear β-catenin zone, surrounded by Notch1 positive dermal cells, induces Jagged1. Inhibition of Notch signaling disrupts the spatial configuration of the nuclear β-catenin zone and leads to randomized feather polarity. Mathematical modeling predicts that lateral inhibition, mediated by Notch signaling, functions to reduce Wnt7a gradient variations and fluctuations to form the sharp boundary observed for the dermal β-catenin zone. This zone is also enriched for nonmuscle myosin IIB. Suppressing nonmuscle myosin IIB disrupts directional cell rearrangements and abolishes feather bud elongation. These data suggest that a unique molecular module involving chemical-mechanical coupling converts a pliable chemical gradient to a precise domain, ready for subsequent mechanical action, thus defining the position, boundary, and duration of localized morphogenetic activity that molds the shape of growing organs.anterior-posterior axial orientation | boundary formation | denoising | morphogen gradient

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“…Koike and colleagues used in vitro studies to show that the C-tail fragment alone could enter and exit the nucleus, although the mechanism remained unexplored (29). Given that fluorescence recovery after photobleaching (FRAP) assays showed that in live mammalian cells full-length -catenin can enter and exit the nucleus at the rate of seconds to minutes (30)(31)(32) the potential role of the tail sequences in nuclear transport was re-evaluated. Here we show that the unstructured N-and C-tails, although sharing no common amino acid sequence with the central armadillo repeats, also contacted the NPC to mediate rapid and receptor-independent transport of -catenin and competed with importin-for transit through the NPC.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: The hydrophobic rich N- and C-terminal tails of beta-catenin facilitate nuclear import of beta-catenin

et al. 2014

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Regulation of β‐Catenin Nuclear Dynamics by GSK‐3β Involves a LEF‐1 Positive Feedback Loop

Cited by 50 publications

References 44 publications

Specific Armadillo Repeat Sequences Facilitate β-Catenin Nuclear Transport in Live Cells via Direct Binding to Nucleoporins Nup62, Nup153, and RanBP2/Nup358

Specific Armadillo Repeat Sequences Facilitate β-Catenin Nuclear Transport in Live Cells via Direct Binding to Nucleoporins Nup62, Nup153, and RanBP2/Nup358

Shaping organs by a wingless-int/Notch/nonmuscle myosin module which orients feather bud elongation

WITHDRAWN: The hydrophobic rich N- and C-terminal tails of beta-catenin facilitate nuclear import of beta-catenin

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