Complex Formation between S100B Protein and the p90 Ribosomal S6 Kinase (RSK) in Malignant Melanoma Is Calcium-dependent and Inhibits Extracellular Signal-regulated Kinase (ERK)-mediated Phosphorylation of RSK*

Background: S100B is overexpressed in malignant melanoma and contributes to cancer progression. Results: The S100B-RSK complex was found to be Ca2+-dependent, block phosphorylation of RSK at Thr-573, and sequester RSK to the cytosol. Conclusion: The Ca2+-dependent S100B-RSK complex provides a new link between the MAPK and Ca2+ signaling pathways. Significance: S100B inhibitors may restore normal MAPK and Ca2+ signaling in malignant melanoma. S100B is a prognostic marker for malignant melanoma. Increasing S100B levels are predictive of advancing disease stage, increased recurrence, and low overall survival in malignant melanoma patients. Using S100B overexpression and shRNAS100B knockdown studies in melanoma cell lines, elevated S100B was found to enhance cell viability and modulate MAPK signaling by binding directly to the p90 ribosomal S6 kinase (RSK). S100B-RSK complex formation was shown to be Ca2+-dependent and to block ERK-dependent phosphorylation of RSK, at Thr-573, in its C-terminal kinase domain. Additionally, the overexpression of S100B sequesters RSK into the cytosol and prevents it from acting on nuclear targets. Thus, elevated S100B contributes to abnormal ERK/RSK signaling and increased cell survival in malignant melanoma.

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