Noncanonical Mode of ERK Action Controls Alternative αβ and γδ T Cell Lineage Fates

•ERK phosphorylation of conventional substrates is dispensable for γδ development•ERK promotes γδ development through an alternate DBP-domain-mediated mechanism•DBP-mediated interactions promote γδ development by increasing protein stability•DBP-mediated interactions are required for positive selection of αβ progenitors

SummaryGradations 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 γδ T cells. Instead, development of γδ 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 γδ fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes.

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