title: A mechanism for SRC kinase-dependent signaling by noncatalytic receptors.
abstract: A fundamental issue in cell biology is how signals are transmitted across membranes. A variety of transmembrane receptors, including multichain immune recognition receptors, lack catalytic activity and require Src family kinases (SFKs) for signal transduction. However, many receptors only bind and activate SFKs after ligand-induced receptor dimerization. This presents a conundrum: How do SFKs sense the dimerization of receptors to which they are not already bound? Most proposals for resolving this enigma invoke additional players, such as lipid rafts or receptor conformational changes. Here we used simple thermodynamics to show that SFK activation is a natural outcome of clustering of receptors with SFK phosphorylation sites, provided that there is phosphorylation-dependent receptor-SFK association and an SFK bound to one receptor can phosphorylate the second receptor or its associated SFK in a dimer. A simple system of receptor, SFK, and an unregulated protein tyrosine phosphatase (PTP) can account for ligand-induced changes in phosphorylation observed in cells. We suggest that a core signaling system comprising a receptor with SFK phosphorylation sites, an SFK, and an unregulated PTP provides a robust mechanism for transmembrane signal transduction. Other events that regulate signaling in specific cases may have evolved for fine-tuning of this basic mechanism.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: Department of Applied Mathematics, University of Washington, Seattle, Washington 98195.
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
mesh_terms: D000818:Animals; D002384:Catalysis; D019281:Dimerization; D004789:Enzyme Activation; D025461:Feedback, Physiological; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D019061:src-Family Kinases