Neu differentiation factor stimulates phosphorylation and activation of the Sp1 transcription factor

Neu differentiation factors (NDFs), or neuregulins, are epidermal growth fa ctor-like growth factors which bind to two tyrosine kinase receptors, ErbB- 3 and ErbB-4. The transcription of several genes is regulated by neuregulin s, including genes encoding specific subunits of the acetylcholine receptor at the neuromuscular junction. Here, we have examined the promoter of the acetylcholine receptor epsilon subunit and delineated a minimal CA-rich seq uence which mediates transcriptional activation by NDF (NDF-response elemen t [NRE]). Using gel mobility shift analysis with an NRE oligonucleotide, we detected two complexes that are induced by treatment with neuregulin and o ther growth factors end identified Sp1, a constitutively expressed zinc fin ger phosphoprotein, as a component of one of these complexes. Phosphatase t reatment, two-dimensional gel electrophoresis, and an in-gel kinase assay i ndicated that Sp1 is phosphorylated by a 60-kDa kinase in response to NDF-i nduced signals. Moreover, Sp1 seems to act downstream of all members of the ErbB family and thus may funnel the signaling of the ErbB network into the nucleus.