Nucleolar localization of a netrin-1 isoform enhances tumor cell proliferation.

Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to be due to the ability of this secreted cue to stimulate survival when bound to its receptors. We showed that in contrast to full-length, secreted netrin-1, some cancer cells produced a truncated intranuclear form of netrin-1 (ΔN-netrin-1) through an alternative internal promoter. Because of a nucleolar localization signal located in its carboxyl terminus, ΔN-netrin-1 was targeted to the nucleolus, where it interacted with nucleolar proteins, affected nucleolar ultrastructure, and interacted with the promoters of ribosomal genes. Moreover, ΔN-netrin-1 stimulated cell proliferation in vitro and tumor growth in vivo. Thus, some cancer cells produce not only a full-length, secreted form of netrin-1 that promotes cell survival but also a truncated netrin-1 that stimulates cell proliferation, potentially by enhancing ribosome biogenesis.