The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis

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Abstract

The development of colonic carcinoma is associated with the mutation of a specific set of genes [1].One of these, DCC (deleted in colorectal cancer) [2-5], is a candidate tumour-suppressor gene, and encodes a receptor for netrin-1, a molecule involved in axon guidance [6-8]. Loss of DCC expression in tumours is not restricted to colon carcinoma [2], and, although there is no increase in the frequency of tumour formation in DCC hemizygous mice [5], reestablishment of DCC expression suppresses tumorigenicity [3,4]. However, the mechanism of action of DCC is unknown. Here we show that DCC induces apoptosis in the absence of ligand binding, but blocks apoptosis when engaged by netrin-1. Furthermore, DCC is a caspase substrate, and mutation of the site at which caspace-3 cleaves DCC suppresses the pro-apoptotic effect of DCC completely. These results indicate that DCC may function as a tumour-suppressor protein by inducing apoptosis in settings in which ligand is unavailable (for example, during metastasis or tumour growth beyond local blood supply) through functional caspase cascades by a mechanism that requires cleavage of DCC at Asp 1,290.

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