NDLI: Different Raf protein kinases mediate different signaling pathways to stimulate E3 ligase RFFL gene expression in cell migration regulation.

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Different Raf protein kinases mediate different signaling pathways to stimulate E3 ligase RFFL gene expression in cell migration regulation.

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Different Raf protein kinases mediate different signaling pathways to stimulate E3 ligase RFFL gene expression in cell migration regulation.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kreutz, Barry Patel, Maulik Kozasa, Tohru Wang, Chen Zhou, Maggie Wu, Dianqing Gan, Xiaoqing
Description	Author Affiliation: Gan X ( From the Department of Pharmacology and Program in Vascular Biology and Therapeutics, Yale School of Medicine, New Haven, Connecticut 06520.)
Abstract	We previously characterized a G 12-specific signaling pathway that stimulates the transcription of the E3 ligase RFFL via the protein kinase ARAF and ERK. This pathway leads to persistent PKC activation and is important for sustaining fibroblast migration. However, questions remain regarding how G 12 specifically activates ARAF, which transcription factor is involved in G 12-mediated RFFL expression, and whether RFFL is important for cell migration stimulated by other signaling mechanisms that can activate ERK. In this study, we show that replacement of the G 12 residue Arg-264 with Gln, which is the corresponding G 13 residue, abrogates the ability of G 12 to interact with or activate ARAF. We also show that G 12 can no longer interact with and activate an ARAF mutant with its C-terminal sequence downstream of the kinase domain being replaced with the corresponding CRAF sequence. These results explain why G 12, but not G 13, specifically activates ARAF but not CRAF. Together with our finding that recombinant G 12 is sufficient for stimulating the kinase activity of ARAF, this study reveals an ARAF activation mechanism that is different from that of CRAF. In addition, we show that this G 12-ARAF-ERK pathway stimulates RFFL transcription through the transcription factor c-Myc. We further demonstrate that EGF, which signals through CRAF, and an activated BRAF mutant also activate PKC and stimulate cell migration through up-regulating RFFL expression. Thus, RFFL-mediated PKC activation has a broad significance in cell migration regulation.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	47
Volume Number	288
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2013-11-22
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cell Movement Physiology Gene Expression Regulation, Enzymologic MAP Kinase Signaling System Ubiquitin-Protein Ligases Biosynthesis Raf Kinases Metabolism Amino Acid Substitution Animals Apoptosis Regulatory Proteins Enzyme Activation Epidermal Growth Factor Genetics GTP-Binding Protein Alpha Subunits, G12-G13 HEK293 Cells Mice Mutation, Missense Protein Kinase C Proto-Oncogene Proteins C-myc Research Support, N.I.H., Extramural Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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