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A BRAF‐MEK complex reveals the molecular basis of oncogenic mutations
Author(s) -
Hymowitz Sarah Gillmor,
Sudhamsu Jawahar,
Haling Jacob,
Peck Ariana,
Yen Ivana,
Morales Tony,
Brandhuber Barbara,
Malek Shiva
Publication year - 2013
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.27.1_supplement.1031.11
Subject(s) - mapk/erk pathway , mek inhibitor , intracellular , signal transduction , kinase , priming (agriculture) , microbiology and biotechnology , extracellular , chemistry , cancer research , biology , botany , germination
The Ras/RAF/MEK/ERK pathway (MAPK pathway) controls intracellular signal transduction downstream of extracellular growth factors and is frequently activated in cancer. Using a combination of crystallographic, biochemical and cellular approaches we show that BRAF forms a stable complex with MEK prior to pathway activation. The BRAF‐MEK kinase domains interact in a tetrameric complex dependent on BRAF dimerization. Formation of this complex is mutually exclusive with either MEK‐KSR or MEK‐MEK interactions. Structural and biochemical evidence illustrate that the molecular determinants for B‐RAF enzymatic activity is distinct from those required for interaction with MEK. Our work also reveals the molecular basis for the paradoxical ability of both BRAF‐activating and –inactivating oncogenic mutations to stimulate the MAPK pathway. Similarly, this data rationalizes the diverse effects of BRAF inhibition by pathway priming of ATP‐competitive BRAF inhibitors.