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BRAF V600E ‐ and PI3′K‐activated signaling pathways cooperate to regulate phosphorylation of ribosomal protein S6 in human melanoma cells
Author(s) -
Silva Jillian M,
McMahon Martin
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.967.8
Subject(s) - p70 s6 kinase 1 , ribosomal s6 kinase , phosphorylation , ribosomal protein s6 , mapk/erk pathway , protein kinase b , cancer research , pi3k/akt/mtor pathway , mek inhibitor , melanoma , signal transduction , v600e , microbiology and biotechnology , chemistry , biology , mutation , biochemistry , gene
The most common genetic alteration in metastatic melanoma is a T1799A transversion encoding BRAF V600E that results in the constitutive activation of the BRAF→MEK→ERK MAP kinase pathway. In many cases, conversion of BRAF V600E expressing melanocytes to melanoma cells also requires activation of PI3′K signaling, usually through silencing of the tumor suppressor PTEN. To explore the mechanisms of cooperation between the BRAF V600E and PI3′K signaling pathways, we applied pharmacological inhibitors of each pathway to BRAF V600E expressing melanoma‐derived cell lines. Our data indicates that blockade of BRAF V600E →MEK→ERK signaling inhibited p70 S6K and ribosomal protein S6 phosphorylation, whereas inhibition of PI3′K suppressed S6 and 4E‐BP1 phosphorylation. In addition, inhibition of BRAF V600E →MEK→ERK or PI3′K blockade also led to the inhibition of melanoma cell proliferation. Moreover, simultaneous inhibition of both the BRAF V600E and PI3′K pathways abrogated the phosphorylation of the cap‐dependent translational regulators, p70 S6K , S6, and 4E‐BP1. However, pharmacological inhibition of the PI3′K effector, AKT, had little effect on cell growth and failed to influence p70 S6K , S6 or 4E‐BP1 phosphorylation. Thus, these results suggest that the regulation of S6 may serve as a downstream integrator of cooperation between the BRAF V600E and PI3′K pathways independent of AKT activation in melanoma cells.