Schwannoma-derived growth factor must be transported into the nucleus to exert its mitogenic activity

Schwannoma-derived growth factor (SDGF) is a mitogen and neurotrophic protein which belongs to the epidermal growth factor (EGF) family. There are two basic amino acid clusters in the SDGF molecule which are homologous to the nuclear targeting signal of the simian virus 40-encoded large tumor antigen. Mutational analysis of these clusters showed that they function as nuclear targeting signals, and a gel retardation assay showed that SDGF binds to A+T-rich DNA sequences. Both the wild-type SDGF and a mutant defective in the nuclear targeting signals activate the immediate early genes NGFI-A and c-fos. The wild-type SDGF is a mitogen for Swiss mouse 3T3 fibroblasts, but the mutant defective in the nuclear targeting signals is not mitogenic. Moreover, wild-type SDGF potentiates [3H]thymidine incorporation in NIH mouse 3T3 cells bearing an EGF receptor defective in the kinase domain, whereas the mutant SDGF does not stimulate DNA synthesis. These results suggest that transport into the nucleus is required for SDGF to induce a mitogenic response.