The processes of T-cell development and activation employ similar immature and mature receptors as well as similar signal transduction pathways to achieve different outcomes. Many signaling molecules are shared between the receptor signaling pathways, including two families of cytoplasmic protein tyrosine kinases, the Src family and the Syk family. The two Syk family members expressed in T cells, Syk and ZAP-70, are structurally similar but are expressed at different times during thymic development and during T-cell activation. These two kinases, although they share many physical features, differ in terms of biochemical activity and regulation. We discuss the overlapping and distinct characteristics of Syk and ZAP-70 in T-cell signaling and the potential biological importance of their differences.

The protein tyrosine phosphatase CD45 is a critical component of the T cell antigen receptor (TCR) signaling pathway, acting as a positive regulator of Src family protein tyrosine kinases (PTKs) such as Lck. Most CD45‐deficient human and murine T cell lines are unable to signal through their TCRs. However, there is a CD45‐deficient cell line that can signal through its TCR. We have studied this cell line to identify a TCR signaling pathway that is independent of CD45 regulation. In the course of these experiments, we found that the Syk PTK, but not the ZAP‐70 PTK, is able to mediate TCR signaling independently of CD45 and of Lck. For this function, Syk requires functional kinase and SH2 domains, as well as intact phosphorylation sites in the regulatory loop of its kinase domain. Thus, differential expression of Syk is likely to explain the paradoxical phenotypes of different CD45‐deficient T cells. Finally, these results suggest differences in activation requirements between two closely related PTK family members, Syk and ZAP‐70. The differential activities of these two kinases suggest that they may play distinct, rather than completely redundant, roles in lymphocyte signaling.

AP-2 transcription factors have been implicated in epidermal biology, but their functional significance has remained elusive. Using conditional knockout technology, we show that AP-2α is essential for governing the balance between growth and differentiation in epidermis. In vivo, epidermis lacking AP-2α exhibits elevated expression of the epidermal growth factor receptor (EGFR) in the differentiating layers, resulting in hyperproliferation when the receptors are activated. Chromatin immunoprecipitation and promoter activity assays identify EGFR as a direct target gene for AP-2α repression, and, in the absence of AP-2α, this is manifested primarily in excessive EGF-dependent phosphoinositol-3 kinase/Akt activity. Together, our findings unveil a hitherto unrecognized repressive role for AP-2α in governing EGFR gene transcription as cells exit the basal layer and withdraw from the cell cycle. These results provide insights into why elevated AP-2α levels are often associated with terminal differentiation and why tumor cells often display reduced AP-2α and elevated EGFR proteins.