γ-Secretase-Regulated Signaling Pathways, such as Notch Signaling, Mediate the Differentiation of Hematopoietic Stem Cells, Development of the Immune System, and Peripheral Immune Responses

Notch signaling mediates the fates of numerous cells in both invertebrates and vertebrates. In the immune system, Notch signaling contributes to the generation of hematopoietic stem cells (HSCs), the promotion of HSC self-renewal, T lineage commitment, intrathymic T cell development, and peripheral lymphocyte differentiation/activation. The intracellular domain (ICD) of Notch is released from the cell membrane by gamma-secretase and translocates to the nucleus to modulate gene expression. Hence, gamma-secretase plays a central role in the regulation of Notch signaling. More than five dozen type 1 transmembrane proteins, including amyloid precursor protein, Notch, and Delta, are substrates for gamma-secretase and their ICDs are released from the cell membrane. Therefore, it is highly possible that mechanisms similar to Notch signaling may widely contribute to gamma-secretase-regulated signaling. Besides Notch, some transmembrane proteins such as CD44 and CSF-1R, which are important for immune responses, have been reported as substrates for gamma-secretase. Since the ICDs of these proteins are also released by gamma-secretase from the cell membrane and localize to the nucleus, it is thought that these ICDs modulate gene expression. Thus, gamma-secretase-regulated signaling, including Notch signaling, may play a wide range of roles in the immune system.