SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF

Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorl...
Ausführliche Beschreibung

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Autor*in:	Feng, Kai [verfasserIn] Shi, Qing Jiao, Dongyue Chen, Yingji Yang, Wanqi Su, Ke Wang, Yalan Huang, Yan Zhang, Pingzhao Li, Yao Wang, Chenji

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	SPOP BRAF Mutation Ubiquitination MAPK/ERK

Anmerkung:	© The Author(s) 2022

Übergeordnetes Werk:	Enthalten in: Cell & bioscience - London : BioMed Central, 2011, 12(2022), 1 vom: 30. Dez.
Übergeordnetes Werk:	volume:12 ; year:2022 ; number:1 ; day:30 ; month:12

Links:	Volltext

DOI / URN:	10.1186/s13578-022-00950-z

Katalog-ID:	SPR051276739

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520			\|a Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway.
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allfields	10.1186/s13578-022-00950-z doi (DE-627)SPR051276739 (SPR)s13578-022-00950-z-e DE-627 ger DE-627 rakwb eng Feng, Kai verfasserin aut SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. SPOP (dpeaa)DE-He213 BRAF (dpeaa)DE-He213 Mutation (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 MAPK/ERK (dpeaa)DE-He213 Shi, Qing aut Jiao, Dongyue aut Chen, Yingji aut Yang, Wanqi aut Su, Ke aut Wang, Yalan aut Huang, Yan aut Zhang, Pingzhao aut Li, Yao aut Wang, Chenji (orcid)0000-0002-5752-6439 aut Enthalten in Cell & bioscience London : BioMed Central, 2011 12(2022), 1 vom: 30. Dez. (DE-627)646079387 (DE-600)2593367-X 2045-3701 nnns volume:12 year:2022 number:1 day:30 month:12 https://dx.doi.org/10.1186/s13578-022-00950-z 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 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 12 2022 1 30 12
spelling	10.1186/s13578-022-00950-z doi (DE-627)SPR051276739 (SPR)s13578-022-00950-z-e DE-627 ger DE-627 rakwb eng Feng, Kai verfasserin aut SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. SPOP (dpeaa)DE-He213 BRAF (dpeaa)DE-He213 Mutation (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 MAPK/ERK (dpeaa)DE-He213 Shi, Qing aut Jiao, Dongyue aut Chen, Yingji aut Yang, Wanqi aut Su, Ke aut Wang, Yalan aut Huang, Yan aut Zhang, Pingzhao aut Li, Yao aut Wang, Chenji (orcid)0000-0002-5752-6439 aut Enthalten in Cell & bioscience London : BioMed Central, 2011 12(2022), 1 vom: 30. Dez. (DE-627)646079387 (DE-600)2593367-X 2045-3701 nnns volume:12 year:2022 number:1 day:30 month:12 https://dx.doi.org/10.1186/s13578-022-00950-z 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 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 12 2022 1 30 12
allfields_unstemmed	10.1186/s13578-022-00950-z doi (DE-627)SPR051276739 (SPR)s13578-022-00950-z-e DE-627 ger DE-627 rakwb eng Feng, Kai verfasserin aut SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. SPOP (dpeaa)DE-He213 BRAF (dpeaa)DE-He213 Mutation (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 MAPK/ERK (dpeaa)DE-He213 Shi, Qing aut Jiao, Dongyue aut Chen, Yingji aut Yang, Wanqi aut Su, Ke aut Wang, Yalan aut Huang, Yan aut Zhang, Pingzhao aut Li, Yao aut Wang, Chenji (orcid)0000-0002-5752-6439 aut Enthalten in Cell & bioscience London : BioMed Central, 2011 12(2022), 1 vom: 30. Dez. (DE-627)646079387 (DE-600)2593367-X 2045-3701 nnns volume:12 year:2022 number:1 day:30 month:12 https://dx.doi.org/10.1186/s13578-022-00950-z 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 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 12 2022 1 30 12
allfieldsGer	10.1186/s13578-022-00950-z doi (DE-627)SPR051276739 (SPR)s13578-022-00950-z-e DE-627 ger DE-627 rakwb eng Feng, Kai verfasserin aut SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. SPOP (dpeaa)DE-He213 BRAF (dpeaa)DE-He213 Mutation (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 MAPK/ERK (dpeaa)DE-He213 Shi, Qing aut Jiao, Dongyue aut Chen, Yingji aut Yang, Wanqi aut Su, Ke aut Wang, Yalan aut Huang, Yan aut Zhang, Pingzhao aut Li, Yao aut Wang, Chenji (orcid)0000-0002-5752-6439 aut Enthalten in Cell & bioscience London : BioMed Central, 2011 12(2022), 1 vom: 30. Dez. (DE-627)646079387 (DE-600)2593367-X 2045-3701 nnns volume:12 year:2022 number:1 day:30 month:12 https://dx.doi.org/10.1186/s13578-022-00950-z 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 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 12 2022 1 30 12
allfieldsSound	10.1186/s13578-022-00950-z doi (DE-627)SPR051276739 (SPR)s13578-022-00950-z-e DE-627 ger DE-627 rakwb eng Feng, Kai verfasserin aut SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. SPOP (dpeaa)DE-He213 BRAF (dpeaa)DE-He213 Mutation (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 MAPK/ERK (dpeaa)DE-He213 Shi, Qing aut Jiao, Dongyue aut Chen, Yingji aut Yang, Wanqi aut Su, Ke aut Wang, Yalan aut Huang, Yan aut Zhang, Pingzhao aut Li, Yao aut Wang, Chenji (orcid)0000-0002-5752-6439 aut Enthalten in Cell & bioscience London : BioMed Central, 2011 12(2022), 1 vom: 30. Dez. (DE-627)646079387 (DE-600)2593367-X 2045-3701 nnns volume:12 year:2022 number:1 day:30 month:12 https://dx.doi.org/10.1186/s13578-022-00950-z 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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 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 12 2022 1 30 12
language	English
source	Enthalten in Cell & bioscience 12(2022), 1 vom: 30. Dez. volume:12 year:2022 number:1 day:30 month:12
sourceStr	Enthalten in Cell & bioscience 12(2022), 1 vom: 30. Dez. volume:12 year:2022 number:1 day:30 month:12
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authorswithroles_txt_mv	Feng, Kai @@aut@@ Shi, Qing @@aut@@ Jiao, Dongyue @@aut@@ Chen, Yingji @@aut@@ Yang, Wanqi @@aut@@ Su, Ke @@aut@@ Wang, Yalan @@aut@@ Huang, Yan @@aut@@ Zhang, Pingzhao @@aut@@ Li, Yao @@aut@@ Wang, Chenji @@aut@@
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Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. 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author	Feng, Kai
spellingShingle	Feng, Kai misc SPOP misc BRAF misc Mutation misc Ubiquitination misc MAPK/ERK SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
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topic_title	SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF SPOP (dpeaa)DE-He213 BRAF (dpeaa)DE-He213 Mutation (dpeaa)DE-He213 Ubiquitination (dpeaa)DE-He213 MAPK/ERK (dpeaa)DE-He213
topic	misc SPOP misc BRAF misc Mutation misc Ubiquitination misc MAPK/ERK
topic_unstemmed	misc SPOP misc BRAF misc Mutation misc Ubiquitination misc MAPK/ERK
topic_browse	misc SPOP misc BRAF misc Mutation misc Ubiquitination misc MAPK/ERK
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title	SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
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title_full	SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
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journal	Cell & bioscience
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author_browse	Feng, Kai Shi, Qing Jiao, Dongyue Chen, Yingji Yang, Wanqi Su, Ke Wang, Yalan Huang, Yan Zhang, Pingzhao Li, Yao Wang, Chenji
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author-letter	Feng, Kai
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title_sort	spop inhibits braf-dependent tumorigenesis through promoting non-degradative ubiquitination of braf
title_auth	SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
abstract	Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. © The Author(s) 2022
abstractGer	Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. © The Author(s) 2022
abstract_unstemmed	Background The gene encoding the E3 ubiquitin ligase substrate-binding adapter Speckle-type BTB/POZ protein (SPOP) is frequently mutated in prostate cancer (PCa) and endometrial cancer (EC); however, the molecular mechanisms underlying the contribution of SPOP mutations to tumorigenesis remain poorly understood. Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. Conclusions Our findings provide new insights into the molecular link between SPOP mutation-driven tumorigenesis and aberrant BRAF-dependent activation of the MAPK/ERK pathway. © The Author(s) 2022
collection_details	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_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 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
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title_short	SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF
url	https://dx.doi.org/10.1186/s13578-022-00950-z
remote_bool	true
author2	Shi, Qing Jiao, Dongyue Chen, Yingji Yang, Wanqi Su, Ke Wang, Yalan Huang, Yan Zhang, Pingzhao Li, Yao Wang, Chenji
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up_date	2024-07-03T20:52:21.054Z
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Methods BRAF harbors a potential SPOP-binding consensus motif (SBC) motif. Co-immunoprecipitation assays demonstrated that BRAF interacts with SPOP. A series of functional analyses in cell lines were performed to investigate the biological significance of MAPK/ERK activation caused by SPOP mutations. Results Cytoplasmic SPOP binds to and induces non-degradative ubiquitination of BRAF, thereby reducing the interaction between BRAF and other core components of the MAPK/ERK pathway. SPOP ablation increased MAPK/ERK activation. EC- or PCa-associated SPOP mutants showed a reduced capacity to bind and ubiquitinate BRAF. Moreover, cancer-associated BRAF mutations disrupted the BRAF-SPOP interaction and allowed BRAF to evade SPOP-mediated ubiquitination, thereby upregulating MAPK/ERK signaling and enhancing the neoplastic phenotypes of cancer cells. 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SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF

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