Characterization of Ser338 Phosphorylation for Raf-1 Activation

Zang, Mengwei; Gong, Jun; Luo, Lingqi; Zhou, Jing; Xiang, Xiaoqin; Huang, Wei; Huang, Qiren; Luo, Xianglong; Olbrot, Martin; Peng, Yiru; Chen, Changyan; Luo, Zhijun

doi:10.1074/jbc.m802855200

Cited by 58 publications

(60 citation statements)

References 64 publications

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“…MC204941 and MC205276). The full-length Fgf21 or RAR␤ cDNA was amplified by PCR and subcloned into the shuttle vector pShuttle-CMV, as described previously (22)(23)(24)(25). The resultant plasmids were linearized by the restriction endonuclease PmeI and purified using phenol/chloroform.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting Analysis-Mouse liver tissues or cultured cells were lysed at 4°C in lysis buffer (20 mM Tris-HCl, pH 8.0, 1% (v/v) Nonidet P-40, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM sodium orthovanadate, 25 mM ␤-glycerol phosphate, 1 mM dithiothreitol, 1 mM phenylmethylsulfonyl fluoride, 2 g/ml aprotinin, 2 g/ml leupeptin, and 1 g/ml pepstatin) and subjected to immunoblotting analysis as described previously (22)(23)(24)31).…”

Section: Methodsmentioning

confidence: 99%

“…Cell Treatment and Small RNA Interference-Human HepG2 cells were cultured as described previously (23)(24)(25)31 Dual Luciferase Activity Assays-Cells were transfected with 0.5 g of reporter plasmids, including human FGF21-Luc and 3XRARE-Luc, along with 40 ng of Renilla luciferase plasmid pRL-SV40 (Promega) as an internal control in a 12-well plate. Thirty-two hours post-transfection, cells were treated with either agonists or antagonists of RAR or PPAR␣ as described previously (24).…”

Section: Methodsmentioning

confidence: 99%

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Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

Wong

Walsh

et al. 2013

Journal of Biological Chemistry

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Background: All-trans-retinoic acid ameliorates glucose intolerance and insulin resistance in diabetes. Results: The gene transcription of hepatic Fgf21 and its metabolic effects on lipid oxidation, ketogenesis, and whole-body energy expenditure are up-regulated by RAR␤ activation. Conclusion: Hepatic RAR␤ stimulates FGF21 production via the RARE. Significance: The hepatic RAR-FGF21 axis is a potential druggable target for treating metabolic syndrome.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

Wong

Walsh

et al. 2013

Journal of Biological Chemistry

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“…This configuration of the NtA motif primes BRAF for activation, which may explain why single mutations of BRAF, such as V600E in the activation loop, can cause full activation and drive cancer, while RAF1 mutations are rare in cancer 9. There is no consensus on which kinase phosphorylates the NtA motif in vivo, since several kinases, including RAF1 itself, have been reported to be able to do this 1, 10. As shown by mutagenesis studies,7 the NtA motif in the activator is required for transactivation of the receiver in RAF dimers.…”

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confidence: 99%

Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

et al. 2015

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RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N‐terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC‐helix and charged residues upstream of the NtA motif. Additionally, we show that the R‐spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure‐based mechanism for the auto‐transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization‐related drug resistance.

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“…The kinases that can be involved in the phosphorylation of Tyr341 include the Src (47,17) and JAK family kinases (Janus Kinase) (48) . Phosphorylation of Tyr340/341 stimulated by growth factor requires Ras-dependent membrane recruitment and Src family tyrosine kinases (18,19,40,45) , and phosphorylation of Tyr340/341 and Ser338 is required for maximal Raf activity (4,8,43,44) . Mutation of Tyr341 severely compromises Raf-1 kinase activity (47,17) .…”

Section: Ras-dependent Activation Of Raf Kinasementioning

confidence: 99%

Raf kinases in signal transduction and interaction with translation machinery

Migliaccio

Sanges

Ruggiero

et al. 2013

BioMolecular Concepts

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Abstract:In recent years, a large amount of evidence has given a central role to translational control in diseases such as cancer, tissue hypertrophy and neurodegeneration. Its deregulation can directly modulate cell cycling, transformation and survival response. The aim of this review is to describe the interaction between Raf activation and the main characters of the translational machinery, such as the elongation factor 1A (eEF1A), which has been recognized in recent years as one of the most interesting putative oncogenes. A particular emphasis is given to an intriguing non-canonical role that eEF1A can play in the relationship between the Ras → Raf-1 → MEK1 → ERK-1/2 and PI3K → Akt signaling pathways. Recently, our group has described a C-Raf kinase-mediated phosphorylation of eEF1A triggered by a survival pathway induced upon interferon alpha (IFN α ) treatment in the human epidermoid cancer cell line (H1355). This phosphorylation seems to be the center of the survival pathway that counteracts the well-known pro-apoptotic function of IFN α . Furthermore, we have identified two new phosphorylation sites on eEF1A (Ser21 and Thr88) that are substrates for Raf kinases in vitro and, likely, in vivo as well. These residues seem to have a significant functional role in the control of cellular processes, such as cell proliferation and survival. In fact, overexpression of eEF1A2 in gemcitabine-treated cancer cells caused the upregulation of phosphoAkt and an increase in cell viability, thereby suggesting that eEF1A2 could exert its oncogenic behavior by participating in the regulation of PI3K pathway.

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Characterization of Ser338 Phosphorylation for Raf-1 Activation

Cited by 58 publications

References 64 publications

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

Raf kinases in signal transduction and interaction with translation machinery

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