RanBPM is an inhibitor of ERK signaling.

Ran-binding protein M (RanBPM) is a nucleocytoplasmic protein of yet unknown function. We have previously shown that RanBPM inhibits expression of the anti-apoptotic factor Bcl-2 and promotes apoptosis induced by DNA damage. Here we show that the effects of RanBPM on Bcl-2 expression occur through a regulation of the ERK ...
signaling pathway. Transient and stable down-regulation of RanBPM stimulated ERK phosphorylation, leading to Bcl-2 up-regulation, while re-expression of RanBPM reversed these effects. RanBPM was found to inhibit MEK and ERK activation induced by ectopic expression of active RasV12. Activation of ERK by active c-Raf was also prevented by RanBPM. Expression of RanBPM correlated with a marked decrease in the protein levels of ectopically expressed active c-Raf and also affected the expression of endogenous c-Raf. RanBPM formed a complex with both active c-Raf, consisting of the C-terminal kinase domain, and endogenous c-Raf in mammalian cells. In addition, RanBPM was found to decrease the binding of Hsp90 to c-Raf. Finally, we show that loss of RanBPM expression confers increased cell proliferation and cell migration properties to HEK293 cells. Altogether, these findings establish RanBPM as a novel inhibitor of the ERK pathway through an interaction with the c-Raf complex and a regulation of c-Raf stability, and provide evidence that RanBPM loss of expression results in constitutive activation of the ERK pathway and promotes cellular events leading to cellular transformation and tumorigenesis.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Apoptosis, Cell Movement, Cell Proliferation, Cell Transformation, Neoplastic, Cytoskeletal Proteins, DNA Damage, Gene Expression Regulation, Neoplastic, HEK293 Cells, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase Kinases, Nuclear Proteins, Phosphorylation, Protein Binding, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-raf
PLoS ONE
Date: Nov. 03, 2012
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