R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis

R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this stud...
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Autor*in:	Tan, Lifeng [verfasserIn] Yan, Mengfang Su, Zijie Wang, Hanbin Li, Huan Zhao, Xibao Liu, Shanshan Zhang, Long Sun, Qi Lu, Desheng

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	Axin CK1ε LRP6 RSPO1 Wnt/β-catenin signaling

Anmerkung:	© The Author(s) 2024

Übergeordnetes Werk:	Enthalten in: Cell communication and signaling - London : Biomed Central, 2003, 22(2024), 1 vom: 05. Jan.
Übergeordnetes Werk:	volume:22 ; year:2024 ; number:1 ; day:05 ; month:01

Links:	Volltext

DOI / URN:	10.1186/s12964-023-01456-y

Katalog-ID:	SPR054282055

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520			\|a R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract
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Indexfelder

author_variant	l t lt m y my z s zs h w hw h l hl x z xz s l sl l z lz q s qs d l dl
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allfields	10.1186/s12964-023-01456-y doi (DE-627)SPR054282055 (SPR)s12964-023-01456-y-e DE-627 ger DE-627 rakwb eng Tan, Lifeng verfasserin aut R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract Axin (dpeaa)DE-He213 CK1ε (dpeaa)DE-He213 LRP6 (dpeaa)DE-He213 RSPO1 (dpeaa)DE-He213 Wnt/β-catenin signaling (dpeaa)DE-He213 Yan, Mengfang aut Su, Zijie aut Wang, Hanbin aut Li, Huan aut Zhao, Xibao aut Liu, Shanshan aut Zhang, Long aut Sun, Qi aut Lu, Desheng aut Enthalten in Cell communication and signaling London : Biomed Central, 2003 22(2024), 1 vom: 05. Jan. (DE-627)37375275X (DE-600)2126315-2 1478-811X nnns volume:22 year:2024 number:1 day:05 month:01 https://dx.doi.org/10.1186/s12964-023-01456-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 05 01
spelling	10.1186/s12964-023-01456-y doi (DE-627)SPR054282055 (SPR)s12964-023-01456-y-e DE-627 ger DE-627 rakwb eng Tan, Lifeng verfasserin aut R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract Axin (dpeaa)DE-He213 CK1ε (dpeaa)DE-He213 LRP6 (dpeaa)DE-He213 RSPO1 (dpeaa)DE-He213 Wnt/β-catenin signaling (dpeaa)DE-He213 Yan, Mengfang aut Su, Zijie aut Wang, Hanbin aut Li, Huan aut Zhao, Xibao aut Liu, Shanshan aut Zhang, Long aut Sun, Qi aut Lu, Desheng aut Enthalten in Cell communication and signaling London : Biomed Central, 2003 22(2024), 1 vom: 05. Jan. (DE-627)37375275X (DE-600)2126315-2 1478-811X nnns volume:22 year:2024 number:1 day:05 month:01 https://dx.doi.org/10.1186/s12964-023-01456-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 05 01
allfields_unstemmed	10.1186/s12964-023-01456-y doi (DE-627)SPR054282055 (SPR)s12964-023-01456-y-e DE-627 ger DE-627 rakwb eng Tan, Lifeng verfasserin aut R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract Axin (dpeaa)DE-He213 CK1ε (dpeaa)DE-He213 LRP6 (dpeaa)DE-He213 RSPO1 (dpeaa)DE-He213 Wnt/β-catenin signaling (dpeaa)DE-He213 Yan, Mengfang aut Su, Zijie aut Wang, Hanbin aut Li, Huan aut Zhao, Xibao aut Liu, Shanshan aut Zhang, Long aut Sun, Qi aut Lu, Desheng aut Enthalten in Cell communication and signaling London : Biomed Central, 2003 22(2024), 1 vom: 05. Jan. (DE-627)37375275X (DE-600)2126315-2 1478-811X nnns volume:22 year:2024 number:1 day:05 month:01 https://dx.doi.org/10.1186/s12964-023-01456-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 05 01
allfieldsGer	10.1186/s12964-023-01456-y doi (DE-627)SPR054282055 (SPR)s12964-023-01456-y-e DE-627 ger DE-627 rakwb eng Tan, Lifeng verfasserin aut R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract Axin (dpeaa)DE-He213 CK1ε (dpeaa)DE-He213 LRP6 (dpeaa)DE-He213 RSPO1 (dpeaa)DE-He213 Wnt/β-catenin signaling (dpeaa)DE-He213 Yan, Mengfang aut Su, Zijie aut Wang, Hanbin aut Li, Huan aut Zhao, Xibao aut Liu, Shanshan aut Zhang, Long aut Sun, Qi aut Lu, Desheng aut Enthalten in Cell communication and signaling London : Biomed Central, 2003 22(2024), 1 vom: 05. Jan. (DE-627)37375275X (DE-600)2126315-2 1478-811X nnns volume:22 year:2024 number:1 day:05 month:01 https://dx.doi.org/10.1186/s12964-023-01456-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 05 01
allfieldsSound	10.1186/s12964-023-01456-y doi (DE-627)SPR054282055 (SPR)s12964-023-01456-y-e DE-627 ger DE-627 rakwb eng Tan, Lifeng verfasserin aut R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2024 R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract Axin (dpeaa)DE-He213 CK1ε (dpeaa)DE-He213 LRP6 (dpeaa)DE-He213 RSPO1 (dpeaa)DE-He213 Wnt/β-catenin signaling (dpeaa)DE-He213 Yan, Mengfang aut Su, Zijie aut Wang, Hanbin aut Li, Huan aut Zhao, Xibao aut Liu, Shanshan aut Zhang, Long aut Sun, Qi aut Lu, Desheng aut Enthalten in Cell communication and signaling London : Biomed Central, 2003 22(2024), 1 vom: 05. Jan. (DE-627)37375275X (DE-600)2126315-2 1478-811X nnns volume:22 year:2024 number:1 day:05 month:01 https://dx.doi.org/10.1186/s12964-023-01456-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 22 2024 1 05 01
language	English
source	Enthalten in Cell communication and signaling 22(2024), 1 vom: 05. Jan. volume:22 year:2024 number:1 day:05 month:01
sourceStr	Enthalten in Cell communication and signaling 22(2024), 1 vom: 05. Jan. volume:22 year:2024 number:1 day:05 month:01
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Axin CK1ε LRP6 RSPO1 Wnt/β-catenin signaling
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container_title	Cell communication and signaling
authorswithroles_txt_mv	Tan, Lifeng @@aut@@ Yan, Mengfang @@aut@@ Su, Zijie @@aut@@ Wang, Hanbin @@aut@@ Li, Huan @@aut@@ Zhao, Xibao @@aut@@ Liu, Shanshan @@aut@@ Zhang, Long @@aut@@ Sun, Qi @@aut@@ Lu, Desheng @@aut@@
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author	Tan, Lifeng
spellingShingle	Tan, Lifeng misc Axin misc CK1ε misc LRP6 misc RSPO1 misc Wnt/β-catenin signaling R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis
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topic_title	R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis Axin (dpeaa)DE-He213 CK1ε (dpeaa)DE-He213 LRP6 (dpeaa)DE-He213 RSPO1 (dpeaa)DE-He213 Wnt/β-catenin signaling (dpeaa)DE-He213
topic	misc Axin misc CK1ε misc LRP6 misc RSPO1 misc Wnt/β-catenin signaling
topic_unstemmed	misc Axin misc CK1ε misc LRP6 misc RSPO1 misc Wnt/β-catenin signaling
topic_browse	misc Axin misc CK1ε misc LRP6 misc RSPO1 misc Wnt/β-catenin signaling
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title	R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis
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title_full	R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis
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author_browse	Tan, Lifeng Yan, Mengfang Su, Zijie Wang, Hanbin Li, Huan Zhao, Xibao Liu, Shanshan Zhang, Long Sun, Qi Lu, Desheng
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author-letter	Tan, Lifeng
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title_sort	r-spondin-1 induces axin degradation via the lrp6-ck1ε axis
title_auth	R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis
abstract	R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract © The Author(s) 2024
abstractGer	R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract © The Author(s) 2024
abstract_unstemmed	R-spondins (RSPOs) are secreted signaling molecules that potentiate the Wnt/β-catenin pathway by cooperating with Wnt ligands. RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. Graphical Abstract © The Author(s) 2024
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title_short	R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis
url	https://dx.doi.org/10.1186/s12964-023-01456-y
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author2	Yan, Mengfang Su, Zijie Wang, Hanbin Li, Huan Zhao, Xibao Liu, Shanshan Zhang, Long Sun, Qi Lu, Desheng
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up_date	2024-07-04T00:51:28.398Z
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RSPO1 is crucial in tissue development and tissue homeostasis. However, the molecular mechanism by which RSPOs activate Wnt/β-catenin signaling remains elusive. In this study, we found that RSPOs could mediate the degradation of Axin through the ubiquitin–proteasome pathway. The results of Co-IP showed that the recombinant RSPO1 protein promoted the interaction between Axin1 and CK1ε. Either knockout of the CK1ε gene or treatment with the CK1δ/CK1ε inhibitor SR3029 caused an increase in Axin1 protein levels and attenuated RSPO1-induced degradation of the Axin1 protein. Moreover, we observed an increase in the number of associations of LRP6 with CK1ε and Axin1 following RSPO1 stimulation. Overexpression of LRP6 further potentiated Axin1 degradation mediated by RSPO1 or CK1ε. In addition, recombinant RSPO1 and Wnt3A proteins synergistically downregulated the protein expression of Axin1 and enhanced the transcriptional activity of the SuperTOPFlash reporter. Taken together, these results uncover the novel mechanism by which RSPOs activate Wnt/β-catenin signaling through LRP6/CK1ε-mediated degradation of Axin. 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R-spondin-1 induces Axin degradation via the LRP6-CK1ε axis

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