Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila.
Raf activation is regulated by tyrosine 510 phosphorylation in Drosophila.
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DOI：
10.1371/journal.pbio.0060128
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发表时间：
2008-05-20
期刊：
影响因子：
9.8
通讯作者：
Li WX
中科院分区：
文献类型：
--
作者：
Xia F;Li J;Hickey GW;Tsurumi A;Larson K;Guo D;Yan SJ;Silver-Morse L;Li WX
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. Receptor tyrosine kinase (RTK)/Ras signaling pathways control many different biological processes during metazoan development. Mutations that disrupt this signaling pathway cause many human diseases, including cancer. The proto-oncoprotein Raf functions downstream of Ras in transducing signals from RTK. Activating mutations in both Ras and Raf have been linked to many types of human cancers. Despite the importance of these oncoproteins in tumorigenesis, the molecular mechanisms of Raf activation remains unresolved. Here, using a genetic screen in Drosophila, we show that the Src homolog Src64B is an activator of Drosophila Raf (Draf) .Src64B phosphorylates tyrosine Y510, in the Draf kinase domain and will activate a full-length Draf, but not a truncated Draf that contains only its kinase domain, suggesting that Y510 phosphorylation may relieve the autoinhibition of full-length Draf. Since Y510 is conserved among all the members of the Raf protein family, its phosphorylation may serve as a mechanism of Raf regulation in general. Phosphorylation of a conserved tyrosine residue located in the kinase domain of Raf family proteins can serve as a mechanism of Raf activation.
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DOI：
10.1073/pnas.95.16.9214
发表时间：
1998-08-04
影响因子：
11.1
作者：
Cutler, RE;Stephens, RM;Morrison, DK
通讯作者：
Morrison, DK
影响因子：
64.8
作者：
King, AJ;Sun, HY;Marshall, MS
通讯作者：
Marshall, MS
影响因子：
2.7
作者：
Baek, KH;Fabian, JR;Ambrosio, L
通讯作者：
Ambrosio, L
影响因子：
11.4
作者：
Cutler, RE;Morrison, DK
通讯作者：
Morrison, DK
影响因子：
5.3
作者：
FABIAN, JR;DAAR, IO;MORRISON, DK
通讯作者：
MORRISON, DK