RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia
RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palm...
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| Autor*in: |
Jian-Gang Ren [verfasserIn] Bowen Xing [verfasserIn] Kaosheng Lv [verfasserIn] Rachel A. O’Keefe [verfasserIn] Mengfang Wu [verfasserIn] Ruoxing Wang [verfasserIn] Kaylyn M. Bauer [verfasserIn] Arevik Ghazaryan [verfasserIn] George M. Burslem [verfasserIn] Jing Zhang [verfasserIn] Ryan M. O’Connell [verfasserIn] Vinodh Pillai [verfasserIn] Elizabeth O. Hexner [verfasserIn] Mark R. Philips [verfasserIn] Wei Tong [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
In: The Journal of Clinical Investigation - American Society for Clinical Investigation, 2022, 133(2023), 12 |
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| Übergeordnetes Werk: |
volume:133 ; year:2023 ; number:12 |
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| Katalog-ID: |
DOAJ091034809 |
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| 520 | |a RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. | ||
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(DE-627)DOAJ091034809 (DE-599)DOAJ636f9f226afa48728696c139c7a0044c DE-627 ger DE-627 rakwb eng Jian-Gang Ren verfasserin aut RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. Cell biology Hematology Medicine R Bowen Xing verfasserin aut Kaosheng Lv verfasserin aut Rachel A. O’Keefe verfasserin aut Mengfang Wu verfasserin aut Ruoxing Wang verfasserin aut Kaylyn M. Bauer verfasserin aut Arevik Ghazaryan verfasserin aut George M. Burslem verfasserin aut Jing Zhang verfasserin aut Ryan M. O’Connell verfasserin aut Vinodh Pillai verfasserin aut Elizabeth O. Hexner verfasserin aut Mark R. Philips verfasserin aut Wei Tong verfasserin aut In The Journal of Clinical Investigation American Society for Clinical Investigation, 2022 133(2023), 12 (DE-627)316004677 (DE-600)2018375-6 15588238 nnns volume:133 year:2023 number:12 https://doaj.org/article/636f9f226afa48728696c139c7a0044c kostenfrei https://doi.org/10.1172/JCI165510 kostenfrei https://doaj.org/toc/1558-8238 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 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_2006 GBV_ILN_2014 GBV_ILN_2021 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 133 2023 12 |
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(DE-627)DOAJ091034809 (DE-599)DOAJ636f9f226afa48728696c139c7a0044c DE-627 ger DE-627 rakwb eng Jian-Gang Ren verfasserin aut RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. Cell biology Hematology Medicine R Bowen Xing verfasserin aut Kaosheng Lv verfasserin aut Rachel A. O’Keefe verfasserin aut Mengfang Wu verfasserin aut Ruoxing Wang verfasserin aut Kaylyn M. Bauer verfasserin aut Arevik Ghazaryan verfasserin aut George M. Burslem verfasserin aut Jing Zhang verfasserin aut Ryan M. O’Connell verfasserin aut Vinodh Pillai verfasserin aut Elizabeth O. Hexner verfasserin aut Mark R. Philips verfasserin aut Wei Tong verfasserin aut In The Journal of Clinical Investigation American Society for Clinical Investigation, 2022 133(2023), 12 (DE-627)316004677 (DE-600)2018375-6 15588238 nnns volume:133 year:2023 number:12 https://doaj.org/article/636f9f226afa48728696c139c7a0044c kostenfrei https://doi.org/10.1172/JCI165510 kostenfrei https://doaj.org/toc/1558-8238 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 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_2006 GBV_ILN_2014 GBV_ILN_2021 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 133 2023 12 |
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(DE-627)DOAJ091034809 (DE-599)DOAJ636f9f226afa48728696c139c7a0044c DE-627 ger DE-627 rakwb eng Jian-Gang Ren verfasserin aut RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. Cell biology Hematology Medicine R Bowen Xing verfasserin aut Kaosheng Lv verfasserin aut Rachel A. O’Keefe verfasserin aut Mengfang Wu verfasserin aut Ruoxing Wang verfasserin aut Kaylyn M. Bauer verfasserin aut Arevik Ghazaryan verfasserin aut George M. Burslem verfasserin aut Jing Zhang verfasserin aut Ryan M. O’Connell verfasserin aut Vinodh Pillai verfasserin aut Elizabeth O. Hexner verfasserin aut Mark R. Philips verfasserin aut Wei Tong verfasserin aut In The Journal of Clinical Investigation American Society for Clinical Investigation, 2022 133(2023), 12 (DE-627)316004677 (DE-600)2018375-6 15588238 nnns volume:133 year:2023 number:12 https://doaj.org/article/636f9f226afa48728696c139c7a0044c kostenfrei https://doi.org/10.1172/JCI165510 kostenfrei https://doaj.org/toc/1558-8238 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 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_2006 GBV_ILN_2014 GBV_ILN_2021 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 133 2023 12 |
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(DE-627)DOAJ091034809 (DE-599)DOAJ636f9f226afa48728696c139c7a0044c DE-627 ger DE-627 rakwb eng Jian-Gang Ren verfasserin aut RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. Cell biology Hematology Medicine R Bowen Xing verfasserin aut Kaosheng Lv verfasserin aut Rachel A. O’Keefe verfasserin aut Mengfang Wu verfasserin aut Ruoxing Wang verfasserin aut Kaylyn M. Bauer verfasserin aut Arevik Ghazaryan verfasserin aut George M. Burslem verfasserin aut Jing Zhang verfasserin aut Ryan M. O’Connell verfasserin aut Vinodh Pillai verfasserin aut Elizabeth O. Hexner verfasserin aut Mark R. Philips verfasserin aut Wei Tong verfasserin aut In The Journal of Clinical Investigation American Society for Clinical Investigation, 2022 133(2023), 12 (DE-627)316004677 (DE-600)2018375-6 15588238 nnns volume:133 year:2023 number:12 https://doaj.org/article/636f9f226afa48728696c139c7a0044c kostenfrei https://doi.org/10.1172/JCI165510 kostenfrei https://doaj.org/toc/1558-8238 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 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_2006 GBV_ILN_2014 GBV_ILN_2021 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 133 2023 12 |
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rab27b controls palmitoylation-dependent nras trafficking and signaling in myeloid leukemia |
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RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia |
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RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. |
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RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. |
| abstract_unstemmed |
RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS–mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers. |
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RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia |
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https://doaj.org/article/636f9f226afa48728696c139c7a0044c https://doi.org/10.1172/JCI165510 https://doaj.org/toc/1558-8238 |
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Bowen Xing Kaosheng Lv Rachel A. O’Keefe Mengfang Wu Ruoxing Wang Kaylyn M. Bauer Arevik Ghazaryan George M. Burslem Jing Zhang Ryan M. O’Connell Vinodh Pillai Elizabeth O. Hexner Mark R. Philips Wei Tong |
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Bowen Xing Kaosheng Lv Rachel A. O’Keefe Mengfang Wu Ruoxing Wang Kaylyn M. Bauer Arevik Ghazaryan George M. Burslem Jing Zhang Ryan M. O’Connell Vinodh Pillai Elizabeth O. Hexner Mark R. Philips Wei Tong |
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