Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 25, Pages 17450-17462Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M709185200
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Identifying 14-3-3 isoform-specific substrates and functions may be of broad relevance to cell signaling research because of the key role played by this family of proteins in many vital processes. A multitude of ligands have been identified, but the extent to which they are isoform-specific is a matter of debate. Herein we demonstrate, both in vitro and in vivo, a specific, functionally relevant interaction of human 14-3-3 gamma with the molecular scaffold KSR1, which is mediated by the C-terminal stretch of 14-3-3 gamma. Specific binding to 14-3-3 gamma protected KSR1 from epidermal growth factor-induced dephosphorylation and impaired its ability to activate ERK2 and facilitate Ras signaling in Xenopus oocytes. Furthermore, RNA interference-mediated inhibition of 14-3-3 gamma resulted in the accumulation of KSR1 in the plasma membrane, all in accordance with 14-3-3 gamma being the cytosolic anchor that keeps KSR1 inactive. We also provide evidence that KSR1-bound 14-3-3 gamma heterodimerized preferentially with selected isoforms and that KSR1 bound monomeric 14- 3-3 gamma. In sum, we have demonstrated ligand discrimination among 14-3-3 isoforms and shed light on molecular mechanisms of 14-3-3 functional specificity and KSR1 regulation.
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