Novel protein kinase C-mediated control of orai1 function in invasive melanoma

Robert Hooper, Xuexin Zhang, Marie Webster, Christina Go, Joseph Kedra, Katie Marchbank, Donald L. Gill, Ashani T. Weeraratna, Mohamed Trebak, Jonathan Soboloff

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

The incidence of malignant melanoma, a cancer of the melanocyte cell lineage, has nearly doubled in the past 20 years. Wnt5A, a key driver of melanoma invasiveness, induces Ca2+ signals. To understand how store-operated calcium entry (SOCE) contributes to Wnt5A-induced malignancy in melanoma models, we examined the expression and function of STIM1 and Orai1 in patient- derived malignant melanoma cells, previously characterized as either highly invasive (metastatic) or noninvasive. Using both fluorescence microscopy and electrophysiological approaches, we show that SOCE is greatly diminished in invasive melanoma compared to its level in noninvasive cell types. However, no loss of expression of any members of the STIM and Orai families was observed in invasive melanoma cells. Moreover, overexpressed wild-type STIM1 and Orai1 failed to restore SOCE in invasive melanoma cells, and we observed no defects in their localization before or after store depletion in any of the invasive cell lines. Importantly, however, we determined that SOCE was restored by inhibition of protein kinase C, a known downstream target of Wnt5A. Furthermore, coexpression of STIM1 with an Orai1 mutant insensitive to protein kinase C-mediated phosphorylation fully restored SOCE in invasive melanoma. These findings reveal a level of control for STIM/Orai function in invasive melanoma not previously reported.

Original languageEnglish (US)
Pages (from-to)2790-2798
Number of pages9
JournalMolecular and cellular biology
Volume35
Issue number16
DOIs
StatePublished - 2015

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Hooper, R., Zhang, X., Webster, M., Go, C., Kedra, J., Marchbank, K., Gill, D. L., Weeraratna, A. T., Trebak, M., & Soboloff, J. (2015). Novel protein kinase C-mediated control of orai1 function in invasive melanoma. Molecular and cellular biology, 35(16), 2790-2798. https://doi.org/10.1128/MCB.01500-14