5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins.

A short, proline-rich region spanning residues 566-577 in human 5-lipoxygenase is a binding site for the Src homology 3 (SH3) domain of growth factor receptor-bound protein 2 (Grb2), an "adaptor" protein for tyrosine kinase-mediated cell signaling. Purified 5-lipoxygenase bound to glutathione S-transferase fusion products of Grb2 and a truncated version ...
of Grb2 containing its SH3 domain. A peptide corresponding to the proline-rich, SH3-binding motif inhibited formation of the 5-lipoxygenase.Grb2 complex in vitro. The peptide also inhibited the redistribution of 5-lipoxygenase from the cytosol to the membrane in intact or permeabilized neutrophils activated by calcium ionophore A23187. 5-Lipoxygenase did not bind to the SH3 domains of other signaling proteins, such as GTPase-activating protein and phospholipase C gamma; however, it bound to certain cytoskeletal proteins including alpha-actinin and actin. 5-Lipoxygenase contains a consensus guanine nucleotide-binding site at residues 296-299, and guanine nucleotides inhibit 5-lipoxygenase activity in vitro. Our results suggest that 5-lipoxygenase may have a previously unrecognized role in tyrosine kinase signaling, distinct from its catalysis of lipid mediator formation. Our results also clarify the molecular basis for compartmentalization and translocation of 5-lipoxygenase in myeloid cells, implying that it binds to proteins other than its activating protein.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Arachidonate 5-Lipoxygenase, Biological Transport, Cytoskeletal Proteins, GRB2 Adaptor Protein, Glutathione Transferase, Guanine Nucleotides, Humans, Molecular Sequence Data, Neutrophils, Oncogene Protein pp60(v-src), Protein Binding, Proteins, Rabbits, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins, Sequence Alignment
J. Biol. Chem.
Date: Sep. 30, 1994
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