Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila
Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) an...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Cutler, Richard E. [verfasserIn] Morrison, Deborah K. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
1997 |
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| Schlagwörter: |
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| Anmerkung: |
© European Molecular Biology Organization 1997 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 16(1997), 8 vom: 15. Apr., Seite 1953-1960 |
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| Übergeordnetes Werk: |
volume:16 ; year:1997 ; number:8 ; day:15 ; month:04 ; pages:1953-1960 |
| Links: |
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| DOI / URN: |
10.1093/emboj/16.8.1953 |
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| Katalog-ID: |
SPR058000038 |
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| 041 | |a eng | ||
| 100 | 1 | |a Cutler, Richard E. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila |
| 264 | 1 | |c 1997 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a © European Molecular Biology Organization 1997 | ||
| 520 | |a Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. | ||
| 650 | 4 | |a activation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a mutation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Raf‐1 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Ras |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a signaling |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Morrison, Deborah K. |e verfasserin |4 aut | |
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| 952 | |d 16 |j 1997 |e 8 |b 15 |c 04 |h 1953-1960 | ||
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1997 |
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1997 |
| allfields |
10.1093/emboj/16.8.1953 doi (DE-627)SPR058000038 (SPR)16.8.1953-e DE-627 ger DE-627 rakwb eng Cutler, Richard E. verfasserin aut Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila 1997 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1997 Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. activation (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Raf‐1 (dpeaa)DE-He213 Ras (dpeaa)DE-He213 signaling (dpeaa)DE-He213 Morrison, Deborah K. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 16(1997), 8 vom: 15. Apr., Seite 1953-1960 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 https://dx.doi.org/10.1093/emboj/16.8.1953 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 16 1997 8 15 04 1953-1960 |
| spelling |
10.1093/emboj/16.8.1953 doi (DE-627)SPR058000038 (SPR)16.8.1953-e DE-627 ger DE-627 rakwb eng Cutler, Richard E. verfasserin aut Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila 1997 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1997 Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. activation (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Raf‐1 (dpeaa)DE-He213 Ras (dpeaa)DE-He213 signaling (dpeaa)DE-He213 Morrison, Deborah K. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 16(1997), 8 vom: 15. Apr., Seite 1953-1960 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 https://dx.doi.org/10.1093/emboj/16.8.1953 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 16 1997 8 15 04 1953-1960 |
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10.1093/emboj/16.8.1953 doi (DE-627)SPR058000038 (SPR)16.8.1953-e DE-627 ger DE-627 rakwb eng Cutler, Richard E. verfasserin aut Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila 1997 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1997 Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. activation (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Raf‐1 (dpeaa)DE-He213 Ras (dpeaa)DE-He213 signaling (dpeaa)DE-He213 Morrison, Deborah K. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 16(1997), 8 vom: 15. Apr., Seite 1953-1960 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 https://dx.doi.org/10.1093/emboj/16.8.1953 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 16 1997 8 15 04 1953-1960 |
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10.1093/emboj/16.8.1953 doi (DE-627)SPR058000038 (SPR)16.8.1953-e DE-627 ger DE-627 rakwb eng Cutler, Richard E. verfasserin aut Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila 1997 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1997 Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. activation (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Raf‐1 (dpeaa)DE-He213 Ras (dpeaa)DE-He213 signaling (dpeaa)DE-He213 Morrison, Deborah K. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 16(1997), 8 vom: 15. Apr., Seite 1953-1960 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 https://dx.doi.org/10.1093/emboj/16.8.1953 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 16 1997 8 15 04 1953-1960 |
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10.1093/emboj/16.8.1953 doi (DE-627)SPR058000038 (SPR)16.8.1953-e DE-627 ger DE-627 rakwb eng Cutler, Richard E. verfasserin aut Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila 1997 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © European Molecular Biology Organization 1997 Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. activation (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Raf‐1 (dpeaa)DE-He213 Ras (dpeaa)DE-He213 signaling (dpeaa)DE-He213 Morrison, Deborah K. verfasserin aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 16(1997), 8 vom: 15. Apr., Seite 1953-1960 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 https://dx.doi.org/10.1093/emboj/16.8.1953 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 16 1997 8 15 04 1953-1960 |
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Enthalten in The EMBO Journal 16(1997), 8 vom: 15. Apr., Seite 1953-1960 volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 |
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Enthalten in The EMBO Journal 16(1997), 8 vom: 15. Apr., Seite 1953-1960 volume:16 year:1997 number:8 day:15 month:04 pages:1953-1960 |
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Cutler, Richard E. @@aut@@ Morrison, Deborah K. @@aut@@ |
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The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. 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Cutler, Richard E. |
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Cutler, Richard E. misc activation misc mutation misc Raf‐1 misc Ras misc signaling Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila |
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Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila activation (dpeaa)DE-He213 mutation (dpeaa)DE-He213 Raf‐1 (dpeaa)DE-He213 Ras (dpeaa)DE-He213 signaling (dpeaa)DE-He213 |
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Cutler, Richard E. Morrison, Deborah K. |
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mammalian raf‐1 is activated by mutations that restore raf signaling in drosophila |
| title_auth |
Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila |
| abstract |
Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. © European Molecular Biology Organization 1997 |
| abstractGer |
Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. © European Molecular Biology Organization 1997 |
| abstract_unstemmed |
Abstract An interaction with the Ras proto‐oncogene product is a requirement for Raf‐1 activation in many signaling cascades. The significance of this interaction is demonstrated by the fact that a mutation preventing the Ras–Raf interaction severely impairs the function of both mammalian (Raf‐1) and Drosophila (D‐Raf) Raf proteins. In D‐Raf, however, dominant intragenic mutations have been identified that suppress the effect of the Ras‐binding site (RBS) mutation. To address the mechanism by which these mutations restore Raf signaling, we have introduced the suppressor mutations into the analogous residues of mammalian Raf‐1. Here, we show that rather than compensating for the RBS mutation by restoring the Ras–Raf‐1 interaction, the suppressor mutations increase the enzymatic and biological activity of Raf‐1, allowing Raf‐1 to signal in the absence of Ras binding. Surprisingly, we find that while one of the suppressor mutations (P181L) increases the basal kinase activity of Raf‐1, it also abolishes the ability of wild‐type Raf‐1 to become activated by Ras. This mutation occurs in the cysteine‐rich domain (CRD) of Raf‐1 and demonstrates the importance of this region for a productive Ras–Raf interaction. Finally, we present evidence that the most activating suppressor mutation (G498S) increases Raf‐1 activity by introducing a novel phosphorylation site into the $ L_{12} $ activation loop of the Raf‐1 kinase domain. © European Molecular Biology Organization 1997 |
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Mammalian Raf‐1 is activated by mutations that restore Raf signaling in Drosophila |
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https://dx.doi.org/10.1093/emboj/16.8.1953 |
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| score |
7.4004946 |