Expression of the p75 neurotrophin receptor (p75(NTR)) in primary melanomas is associated with deeply invasive lesions. In turn, there is expression of high levels of neurotrophins at the invasion front of normal tissue adjacent to brain metastases, thus implicating this growth factor-receptor system in melanoma tumorigenesis. The neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) are potent chemotactic agents for human melanoma cells which express p75(NTR)in vitro. Here we show that the actin-bundling protein fascin specifically interacts with p75(NTR) in an NGF-dependent manner by co-immunoprecipitation and colocalization in melanoma cells that express the two proteins endogenously. In addition, expression of a fascin point mutant at the serine phosphorylation site (serine 39) regulating actin binding abrogates neurotrophin-induced migration. These results suggest a causal role for NGF-mediated dephosphorylation of serine 39 on fascin in mediating actin binding and subsequent melanoma cell migration.