HMGB1 (high-mobility group box 1) protein, a pleiotropic cytokine released by several cell types under physiological and pathological conditions, has been identified as a signal molecule active on A431 cells. Although extracellular HMGB1 itself does not trigger any detectable signalling effect on these cells, it induces an increased susceptibility to EGF (epidermal growth factor) stimulation. Specifically, at concentrations of EGF which promote undetectable or limited cell responses, the addition of sub-nanomolar concentrations of HMGB1 potentiates the effect of EGF by specifically activating a downstream pathway that leads to enhanced cell motility through an increase in Ca2+ influx, activation of extracellular-signal-regulated kinase 1/2 and remodelling of the actin cytoskeleton. These results, which identify extracellular HMGB1 as an activator of human tumour cell migration operating in concert with EGF, have important implications in the search for novel strategies to control tumour progression and metastatic invasion.

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