Presenilin-dependent "gamma-secretase" processing of deleted in colorectal cancer (DCC).

The presenilin-gamma-secretase complex plays a critical role in mediating intramembranous proteolysis of several type I membrane proteins, including beta-amyloid precursor protein (APP) and Notch. We now show that deleted in colorectal cancer (DCC) is subject to proteolysis within the ectodomain segment both in cultured cells and in vivo and that the residual membrane-tethered DCC "stub" is subsequently processed by gamma-secretase to generate a derivative termed DCC-intracellular domain (ICD). The production of DCC-ICD is inhibited by selective gamma-secretase inhibitors, and by the expression of the dominant negative PS1 D385A variant. Moreover, the membrane-tethered DCC "stubs" accumulate to high levels in PS1-deficient embryos. We also demonstrate that expression of a DCC-Gal4 chimera is capable of activating transcription in a luciferase-based reporter assay and this activity is dependent on gamma-secretase activity. Our findings offer the proposal that DCC performs dual roles both as a cell surface receptor that modulates intracellular signaling pathways and as a transcriptional coactivator that relies on gamma-secretase-dependent production and nuclear translocation of the cytoplasmic domain.