Oligomeric forms of the metastasis-related Mts1 (S100A4) protein stimulate neuronal differentiation in cultures of rat hippocampal neurons

Neuronal differentiation and axonal growth are controlled by a variety of factors including neurotrophic factors; extracellular matrix components, and cell adhesion molecules. Here we describe a novel and very efficient neuritogenic factor, the metastasis-related Mts1 protein, belonging to the S100 protein family. The oligomeric but not the dimeric form of Mts1 strongly induces differentiation of cultured hippocampal neurons. A mutant with a single Y75F amino acid substitution, which stabilizes the dimeric form of Mts1, is unable to promote neurite extension. Disulfide bonds do not play an essential role in the Mts1 neuritogenic activity. Mts1-stimulated neurite outgrowth involves activation of phospholipase C and protein kinase C, depends on the intracellular level of Ca2+, and requires activation of the extracellular signal-regulated kinases (ERKs) 1 and 2.