Netrin-1: Interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas

Netrins, a family of laminin-related secreted proteins, have critical roles in axon guidance and cell migration during development. The deleted in col orectal cancer (DCC) protein has been implicated as a netrin-1 receptor com ponent. The expression and function of netrins in adult tissues remain unkn own, and direct interaction of netrin-1 with DCC has not been demonstrated. We cloned the human netrin-1 (NTN1L) gene, mapped it to chromosome 17p12-1 3, and found that it encodes a 604 amino acid protein with 98% identity to mouse netrin-1 and 50% identity with the Caenorhabditis elegans UNC-6 prote in. NTN1L transcripts were detected in essentially all normal adult tissues studied, and markedly reduced or absent NTN1L expression was seen in simil ar to 50% of brain tumors and neuroblastomas. In one neuroblastoma, missens e mutations at highly conserved NTN1L codons were found. Netrin-1 protein c ould be cross-linked to DCC protein on the cell surface, but it did not imm unoprecipitate with DCC in the absence of cross-linking and it failed to bi nd to a soluble fusion protein containing the entire DCC extracellular doma in. Our findings demonstrating NTN1L loss of expression and mutations sugge st that NTN1L alterations may contribute to the development of some cancers . Furthermore, the binding of netrin-1 to DCC appears to depend on the pres ence of a coreceptor or accessory proteins.