The Bcr kinase downregulates Ras signaling by phosphorylating AF-6 and binding to its PDZ domain.

The protein kinase Bcr is a negative regulator of cell proliferation and oncogenic transformation. We identified Bcr as a ligand for the PDZ domain of the cell junction and Ras-interacting protein AF-6. The Bcr kinase phosphorylates AF-6, which subsequently allows efficient binding of Bcr to AF-6, showing that the Bcr ...
kinase is a regulator of the PDZ domain-ligand interaction. Bcr and AF-6 colocalize in epithelial cells at the plasma membrane. In addition, Bcr, AF-6, and Ras form a trimeric complex. Bcr increases the affinity of AF-6 to Ras, and a mutant of AF-6 that lacks a specific phosphorylation site for Bcr shows a reduced binding to Ras. Wild-type Bcr, but not Bcr mutants defective in binding to AF-6, interferes with the Ras-dependent stimulation of the Raf/MEK/ERK pathway. Since AF-6 binds to Bcr via its PDZ domain and to Ras via its Ras-binding domain, we propose that AF-6 functions as a scaffold-like protein that links Bcr and Ras to cellular junctions. We suggest that this trimeric complex is involved in downregulation of Ras-mediated signaling at sites of cell-cell contact to maintain cells in a nonproliferating state.
Mesh Terms:
Amino Acid Sequence, Binding Sites, Cell Division, Cell Line, Down-Regulation, Enzyme Activation, Glutathione Transferase, Humans, Immunoblotting, Kinesin, Ligands, Microscopy, Fluorescence, Mitogen-Activated Protein Kinases, Models, Biological, Models, Genetic, Molecular Sequence Data, Myosins, Oncogene Proteins, Phosphorylation, Plasmids, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcr, Recombinant Fusion Proteins, Sequence Homology, Amino Acid, Signal Transduction, Transfection, ras Proteins
Mol. Cell. Biol.
Date: Jul. 01, 2003
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