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Lee SY , Coffey F , Fahl SP , Peri S , Rhodes M , Cai KQ , Carleton M , Hedrick SM , Fehling HJ , Zuniga-Pflucker JC , Kappes DJ , Wiest DL
Noncanonical Mode of ERK Action Controls Alternative alphabeta and gammadelta T Cell Lineage Fates
Immunity. 2014 Dec 18;41(6) :934-46
PMID: 25526308   
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Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of gammadelta T cells. Instead, development of gammadelta T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the gammadelta fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes.
1097-4180 Lee, Sang-Yun Coffey, Francis Fahl, Shawn P Peri, Suraj Rhodes, Michele Cai, Kathy Q Carleton, Michael Hedrick, Stephen M Fehling, Hans Joerg Zuniga-Pflucker, Juan Carlos Kappes, Dietmar J Wiest, David L P01 AI102853/AI/NIAID NIH HHS/United States R01 AI081314/AI/NIAID NIH HHS/United States Journal Article United States Immunity. 2014 Dec 18;41(6):934-46. doi: 10.1016/j.immuni.2014.10.021. Epub 2014 Nov 28.