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

ABSTRACT The development of colonic carcinoma is associated with the mutation of a specific set of genes1. One of these, _DCC_ (_deleted in colorectal cancer_)2,3,4,5, is a candidate

tumour-suppressor gene, and encodes a receptor for netrin-1, a molecule involved in axon guidance6,7,8. Loss of DCC expression in tumours is not restricted to colon carcinoma2, and, although

there is no increase in the frequency of tumour formation in _DCC_ hemizygous mice5, re-establishment of DCC expression suppresses tumorigenicity3,4. 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 caspase-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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through

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Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE ATYPICAL CADHERIN MUCDHL ANTAGONIZES COLON CANCER FORMATION AND INHIBITS ONCOGENIC SIGNALING THROUGH

MULTIPLE MECHANISMS Article 13 November 2020 NEGATIVE REGULATION OF TGFΒ-INDUCED APOPTOSIS BY _RAC1B_ ENHANCES INTESTINAL TUMOURIGENESIS Article Open access 25 September 2021 DUSP6 REGULATES

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of caspases-3, -6, -7, and -8. _J. Biol. Chem._ 272, 25719–25723 (1997). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank B. Vogelstein and E. Fearon for the DCC

cDNA, M. Tessier-Lavigne for the netrin-1 cDNA, and F. Martin for the REGb cells. This work was supported in part by grants from the NIH and the VivoRx Corporation. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * The Burnham Institute, La Jolla, 92037, California, USA Patrick Mehlen, Shahrooz Rabizadeh, Scott J. Snipas, Nuria Assa-Munt, Guy S. Salvesen & Dale E.

Bredesen * Neuroscience Department, University of California, San Diego, 92093, California, USA Patrick Mehlen, Shahrooz Rabizadeh, Scott J. Snipas, Nuria Assa-Munt, Guy S. Salvesen & 

Dale E. Bredesen Authors * Patrick Mehlen View author publications You can also search for this author inPubMed Google Scholar * Shahrooz Rabizadeh View author publications You can also

search for this author inPubMed Google Scholar * Scott J. Snipas View author publications You can also search for this author inPubMed Google Scholar * Nuria Assa-Munt View author

publications You can also search for this author inPubMed Google Scholar * Guy S. Salvesen View author publications You can also search for this author inPubMed Google Scholar * Dale E.

Bredesen View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Dale E. Bredesen. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Mehlen, P., Rabizadeh, S., Snipas, S. _et al._ The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. _Nature_

395, 801–804 (1998). https://doi.org/10.1038/27441 Download citation * Received: 10 April 1998 * Accepted: 29 July 1998 * Issue Date: 22 October 1998 * DOI: https://doi.org/10.1038/27441

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