A mechanism for SRC kinase-dependent signaling by noncatalytic receptors.

Cooper, Jonathan A and Qian, Hong (2008) A mechanism for SRC kinase-dependent signaling by noncatalytic receptors. Biochemistry, 47 (21). pp. 5681-5688. ISSN 1520-4995

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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.

Item Type:	Article or Abstract
Additional Information:	This article is available to subscribers only via the URL above.
DOI:	10.1021/bi8003044
PubMed ID:	18444664
NIHMSID:	NIHMS47053
PMCID:	PMC2614901
Grant Numbers:	R01 CA041072-23, GM068610
Keywords or MeSH Headings:	Animals; Catalysis; Dimerization; Enzyme Activation; Feedback, Biochemical; Humans; Models, Biological; Phosphorylation; Protein Structure, Tertiary; Signal Transduction; src-Family Kinases/physiology;
Subjects:	Cellular and Organismal Processes > Cell Physiology > Cell communication Molecules > Proteins > Receptors
Depositing User:	Library Staff
Date Deposited:	08 Sep 2008 19:01
Last Modified:	14 Feb 2012 14:42
URI:	http://authors.fhcrc.org/id/eprint/2

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