Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila.
The proto-oncoprotein Raf is pivotal for mitogen-activated protein kinase (MAPK) signaling, and its aberrant activation has been implicated in multiple human cancers. However, the precise molecular mechanism of Raf activation, especially for B-Raf, remains unresolved. By genetic and biochemical stud...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-05-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060128&type=printable |
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| _version_ | 1850240557901676544 |
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| author | Fan Xia Jinghong Li Gavin W Hickey Amy Tsurumi Kimberly Larson Dongdong Guo Shian-Jang Yan Louis Silver-Morse Willis X Li |
| author_facet | Fan Xia Jinghong Li Gavin W Hickey Amy Tsurumi Kimberly Larson Dongdong Guo Shian-Jang Yan Louis Silver-Morse Willis X Li |
| author_sort | Fan Xia |
| collection | DOAJ |
| description | The proto-oncoprotein Raf is pivotal for mitogen-activated protein kinase (MAPK) signaling, and its aberrant activation has been implicated in multiple human cancers. However, the precise molecular mechanism of Raf activation, especially for B-Raf, remains unresolved. By genetic and biochemical studies, we demonstrate that phosphorylation of tyrosine 510 is essential for activation of Drosophila Raf (Draf), which is an ortholog of mammalian B-Raf. Y510 of Draf is phosphorylated by the c-src homolog Src64B. Acidic substitution of Y510 promotes and phenylalanine substitution impairs Draf activation without affecting its enzymatic activity, suggesting that Y510 plays a purely regulatory role. We further show that Y510 regulates Draf activation by affecting the autoinhibitory interaction between the N- and C-terminal fragments of the protein. Finally, we show that Src64B is required for Draf activation in several developmental processes. Together, these results suggest a novel mechanism of Raf activation via Src-mediated tyrosine phosphorylation. Since Y510 is a conserved residue in the kinase domain of all Raf proteins, this mechanism is likely evolutionarily conserved. |
| format | Article |
| id | doaj-art-4036ce6e4cc642a2b53bb3176313e2a3 |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2008-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-4036ce6e4cc642a2b53bb3176313e2a32025-08-20T02:00:50ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852008-05-0165e12810.1371/journal.pbio.0060128Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila.Fan XiaJinghong LiGavin W HickeyAmy TsurumiKimberly LarsonDongdong GuoShian-Jang YanLouis Silver-MorseWillis X LiThe proto-oncoprotein Raf is pivotal for mitogen-activated protein kinase (MAPK) signaling, and its aberrant activation has been implicated in multiple human cancers. However, the precise molecular mechanism of Raf activation, especially for B-Raf, remains unresolved. By genetic and biochemical studies, we demonstrate that phosphorylation of tyrosine 510 is essential for activation of Drosophila Raf (Draf), which is an ortholog of mammalian B-Raf. Y510 of Draf is phosphorylated by the c-src homolog Src64B. Acidic substitution of Y510 promotes and phenylalanine substitution impairs Draf activation without affecting its enzymatic activity, suggesting that Y510 plays a purely regulatory role. We further show that Y510 regulates Draf activation by affecting the autoinhibitory interaction between the N- and C-terminal fragments of the protein. Finally, we show that Src64B is required for Draf activation in several developmental processes. Together, these results suggest a novel mechanism of Raf activation via Src-mediated tyrosine phosphorylation. Since Y510 is a conserved residue in the kinase domain of all Raf proteins, this mechanism is likely evolutionarily conserved.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060128&type=printable |
| spellingShingle | Fan Xia Jinghong Li Gavin W Hickey Amy Tsurumi Kimberly Larson Dongdong Guo Shian-Jang Yan Louis Silver-Morse Willis X Li Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila. PLoS Biology |
| title | Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila. |
| title_full | Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila. |
| title_fullStr | Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila. |
| title_full_unstemmed | Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila. |
| title_short | Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila. |
| title_sort | raf activation is regulated by tyrosine 510 phosphorylation in drosophila |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.0060128&type=printable |
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