ERK2 phosphorylation of serine 77 regulates Bmf pro-apoptotic activity

• Published in: Cell death & disease Vol. 3; no. 1; p. e253
• Main Authors: Shao, Y, Aplin, A E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2012; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/80/458/1733; 631/80/82/23; 631/80/86; 692/699/67/1813/1634; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Cytoplasmic Dyneins - genetics; Cytoplasmic Dyneins - metabolism; Gene Expression Regulation; Humans; Immunology; Life Sciences; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mitochondria - genetics; Mitochondria - metabolism; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Original; original-article; Phosphorylation; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Serine - genetics; Serine - metabolism; Signal Transduction; melanoma; Bmf; ERK2; phosphorylation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2011.137

B-cell lymphoma 2 (Bcl-2) homology 3 (BH3)-only proteins represent a class of pro-apoptotic factors that neutralize pro-survival Bcl-2 proteins, and, in some cases, directly activate Bax. The mechanisms of control and the role of BH3-only proteins, such as Bcl-2 like protein 11 extra large and Bad are well studied. By contrast, relatively little is known about the regulation and role of Bcl-2 modifying factor (Bmf). The B-RAF oncogene is mutated in ∼8% of human tumors. We have previously shown that Bmf is upregulated at the transcript level and is required for apoptosis induced by targeting B-RAF signaling in tumor cells harboring mutant B-RAF. In this study, we show that Bmf is regulated at the post-translational level by mutant B-RAF-MEK-ERK2 signaling. Extracellular signal-regulated kinase (ERK2) directly phosphorylates Bmf on serine 74 and serine 77 residues with serine 77 being the predominant site. In addition, serine 77 phosphorylation reduces Bmf pro-apoptotic activity likely through a mechanism independent of altering Bmf localization to the mitochondria and/or interactions with dynein light chain 2 and the pro-survival proteins, B-cell lymphoma extra large, Bcl-2 and Mcl-1. These data identify a novel mode of regulation in Bmf that modulates its pro-apoptotic activity in mutant B-RAF tumor cells.