ERK signals that promote γδ T cell development require ERK interaction with DEF domain-containing targets (HEM3P.276)

Differential induction of ERK signals has been implicated in numerous fate decisions; however, the molecular basis by which gradations in ERK signaling specify alternate fates remains poorly understood. We report here that divergence of the αβ and γδ T cell fates is dependent upon differences in the extent of T cell receptor (TCR) induced activation of ERK signaling. Adoption of the γδ fate is linked to greater amplitude and duration of ERK activation, but ERK activation does not promote γδ development by phosphorylation of substrates like Rsk. Instead, ERK promotes adoption of the γδ fate by physically interacting with DEF domain containing targets through its DEF binding pocket (DBP). The DEF domain-containing targets include immediate early genes (IEG) such as the transcription factor early growth response gene 1 (Egr1). Egr1 protein is normally unstable, but is stabilized by DEF-DBP mediated interaction with ERK. Thus, ERK signals promote γδ development by stabilizing IEG proteins, including transcription factors, thereby enabling them to transactivate targets not possible in the absence of this increase in stability.