Figure 2.

Integrated model of Ras activation during thymocyte development. At the CD4⁻CD8⁻ (DN)3 stage, ligand-independent pre-T cell receptor (TCR) signals are transmitted to Ras and extracellular signal-regulated kinase (ERK) by the combined actions of son of sevenless 1 (Sos1), Ras guanine nucleotide-releasing protein 1 (RasGRP1), and RasGRP4 to stimulate proliferation and differentiation to the CD4+CD8+ (DP) stage. In the thymic cortex, positively selecting signals are transmitted from the TCR to Ras via RasGRP1. Downstream of Ras, ERK activation is required for efficient positive selection. In the medulla, higher-potency ligands trigger Ras activation via either RasGRP1 or Sos1 to promote negative selection. Here, activation of ERK seems to be dispensable, and activation of other mitogen-activated protein kinases [MAPKs; c-jun N-terminal kinase (JNK), p38, and ERK5] are likely more important. Ras guanine nucleotide exchange factors (GEFs) whose individual deletion blocks thymocyte development for a given signal are shown in red, whereas RasGEFs that require combined deletion with a second RasGEF to cause a developmental block are shown in blue. Proteins whose role at a given developmental checkpoint have not been demonstrated by developmental studies are shown in green.