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

Kira G Hartman,Adam D Pierce,Jennifer M Fox,Michele I Vitolo,Paul Shapiro,Paul T Wilder,David J Weber,Stuart S Martin

doi:10.1074/jbc.m114.561613

Kira G Hartman, Adam D Pierce + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m114.561613

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Abstract

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 shRNA(S100B) 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 Ca(2+)-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.

Highlights

S100B is overexpressed in malignant melanoma and contributes to cancer progression
The 501mel cells were critical for these studies because they do not express detectable levels of S100B, which is a rarity for human malignant melanoma (40, 41)
Increased S100B levels contribute to cancer cell growth and survival as shown here (Fig. 1) and elsewhere (19)

Summary

Background

S100B is overexpressed in malignant melanoma and contributes to cancer progression. Results: The S100B-RSK complex was found to be Ca2ϩ-dependent, block phosphorylation of RSK at Thr-573, and sequester. 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. Elevated S100B contributes to abnormal ERK/RSK signaling and increased cell survival in malignant melanoma. In addition to being a tumor marker, there is evidence that S100B contributes to cancer progression via Ca2ϩ-dependent target interactions that regulate cell growth and survival (6, 9 –13). As part of a feedback loop, the activated N-terminal kinase domain catalyzes a second autophosphorylation event within RSK at Ser-749 to dissociate the ERK-RSK complex and disengage the RSK signaling cascade (35). In addition to repressing the p53-tumor suppressor pathway (9 –11), elevated S100B alters MAPK signaling in malignant melanoma via a direct and Ca2ϩ-dependent interaction with RSK

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION