ShcA and c-Abl provide a new signaling axis regulating beta-selection (63.8)

Abstract

Abstract Progression of immature CD4-CD8- thymocytes through β selection checkpoint is determined by signals from the pre-T cell receptor (pre-TCR) along with signals from Notch. Knockout of the adapter protein ShcA, or transgenic expression of a phosphorylation-defective mutant of ShcA (ShcFFF) leads to a severe block at β selection. Our studies to mechanistically understand the ShcA function showed that ShcA acts upstream of ERK, and the transcription factors Egr-1 and Egr-3 during β selection; however, phospho-ShcA also appeared to be linked to other signaling pathways. We performed a yeast three-hybrid screen, using as bait ShcA that was phosphorylated by Lck. This screen identified binding of c-Abl (via its SH2 domain) to phosphorylated ShcA. During pre TCR dependent signaling, phosphorylation of ShcA was required for optimal c-Abl phosphorylation. Using mice deficient either in c-Abl and/or its homologue Arg, we show that ShcA and c-Abl regulate DN thymocyte proliferation, and the proper localization of DN thymocytes near the thymic cortex. Ectopic expression of a constitutive active c-Abl allowed thymocytes to resume proliferation, differentiation, and CXCR4 dependent migration to SDF-1α. Collectively, these data reveal a previously unappreciated ShcA::c-Abl signaling axis that appears to critically influence thymic β selection.