Nucleo-cytoplasmic shuttling of human Kank protein accompanies intracellular translocation of β-catenin

Wang, Yong; Kakinuma, Naoto; Zhu, Yun; Kiyama, Ryoiti

doi:10.1242/jcs.03169

Cited by 31 publications

(25 citation statements)

References 30 publications

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“…␤-Catenin can exit the nucleus via the CRM1 pathway when bound to specific partners that contain an nuclear export sequence (13)(14)(15)(16)(17). However, the major export route of ␤-catenin is independent of CRM1 (35).…”

Section: Resultsmentioning

confidence: 99%

“…We and others observed that a fraction of ␤-catenin can exit the nucleus indirectly in complex with other proteins (e.g. APC, Kank, LZTS2, Axin) that do access the CRM1/exportin-1 route, at least when these proteins are overexpressed in cells (13)(14)(15)(16)(17). However, when its expression is induced transiently by Wnt signaling or chronically by cancer-linked mutations, the majority of ␤-catenin exits the nucleus independent of CRM1, exogenous soluble factors, and 18).…”

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confidence: 95%

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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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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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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 95%

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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“…KANK2 localized to podocyte cell bodies as well as nuclei in rat glomeruli ( Figure 2B and Supplemental Figure 2B). KANK proteins contain a KN motif, which includes potential nuclear localization and export signals (8), and were shown to shuttle between the nucleus and the cytoplasm via a process mediated by nuclear localization and export signals (13). KANK4 localized to podocyte cell bodies and primary processes ( Figure 2C and Supplemental Figure 2C).…”

Section: Mutations In Kank2 Cause Ns In Humansmentioning

confidence: 99%

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Gee¹,

et al. 2015

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“…As the subcellular localization of a protein is closely related to its function (Andersson et al, 2004;Chung and Eng, 2005;GamaCarvalho and Carmo-Fonseca, 2001;Gomez-Angelats and Cidlowski, 2003;Schickling et al, 2001;Wang et al, 2006;Zhan et al, 2002), we hypothesized that the NLS and NES mutants of cFLIP-L might have a different function from wild-type cFLIP-L. Cells constitutively expressing the wild-type and mutant cFLIP-L proteins (supplementary material Fig.…”

Section: Mutations In the C-terminus Of Cflip-l Abrogate The Activitymentioning

confidence: 99%

Modulation of Wnt signaling by the nuclear localization of cellular FLIP-L

Katayama

Ishioka

Takada

et al. 2010

Journal of Cell Science

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Cellular FLIP (cFLIP) inhibits the apoptosis signaling initiated by death receptor ligation. We previously reported that a long form of cFLIP (cFLIP-L) enhances Wnt signaling via inhibition of β-catenin ubiquitylation. In this report, we present evidence that cFLIP-L translocates into the nucleus, which could have a role in modulation of Wnt signaling. cFLIP-L has a functional bipartite nuclear localization signal (NLS) at the C-terminus. Wild-type cFLIP-L (wt-FLIP-L) localizes in both the nucleus and cytoplasm, whereas NLS-mutated cFLIP-L localizes predominantly in the cytoplasm. cFLIP-L also has a nuclear export signal (NES) near the NLS, and leptomycin B, an inhibitor of CRM1-dependent nuclear export, increases the nuclear accumulation of cFLIP-L, suggesting that it shuttles between the nucleus and cytoplasm. Expression of mutant cFLIP-L proteins with a deletion or mutations in the NLS and NES confers resistance to Fas-mediated apoptosis, as does wt-FLIP-L, but they do not enhance Wnt signaling, which suggests an important role of the C-terminus of cFLIP-L in Wnt-signaling modulation. When wt-FLIP-L is expressed in the cytoplasm by conjugation with exogenous NES (NES-FLIP-L), Wnt signaling is not enhanced, whereas the NES-FLIP-L increases cytoplasmic β-catenin as efficiently as wt-FLIP-L. cFLIP-L physically interacts with the reporter plasmid for Wnt signaling, but not with the control plasmid. These results suggest a role for nuclear cFLIP-L in the modulation of Wnt signaling.

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Nucleo-cytoplasmic shuttling of human Kank protein accompanies intracellular translocation of β-catenin

Cited by 31 publications

References 30 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

KANK deficiency leads to podocyte dysfunction and nephrotic syndrome

Modulation of Wnt signaling by the nuclear localization of cellular FLIP-L

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