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Review
. 2008 May 27;47(21):5681-5688.
doi: 10.1021/bi8003044. Epub 2008 Apr 30.

A mechanism for SRC kinase-dependent signaling by noncatalytic receptors

Jonathan A Cooper #  1 , Hong Qian #  2
Affiliations
Review

A mechanism for SRC kinase-dependent signaling by noncatalytic receptors

Jonathan A Cooper et al. Biochemistry. .

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.

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Figures

FIGURE 1
FIGURE 1. Models for regulation of receptor tyrosine kinases and SFK-dependent non-catalytic receptors
(a) Structure and regulation of SFKs. SFKs have 3 domains: SH3 (blue, phosphorylation-independent binding, not considered here), SH2 (yellow, phosphorylation-dependent binding) and kinase (white, orange or crimson according to increasing activity). The SFK can adopt two main conformation states: "closed" inactive (E†) and "open" low (E) and high (E*) activity forms. E is converted to E* by intermolecular phosphorylation in the activation loop. In addition, phosphorylation at the C terminus alters the balance between the closed and open conformations by stabilizing the closed form. This phosphorylation is not regulated in the model, so is not considered further. (b) Regulation of RTKs. The kinase domains of monomeric RTKs, R, are inhibited by intramolecular interactions, and have low basal activity (orange) which is readily reversed by PTPs. Following dimerization by ligand, L, intermolecular phosphorylation of the activation loop occurs, and the kinase is activated (crimson). If ligand dissociates, monomeric receptors will remain in the phosphorylated, active state until dephosphorylated by PTPs. This allows for hysteresis in signaling. (c) Proposed model for regulation of SDRs. Only a small fraction of monomeric SDRs (R) are phosphorylated. After dimerization by ligand, this phosphorylation may allow binding of an SFK (RR*-E complex). This may lead to an "intramolecular" phosphorylation to form a R*R*-E complex. This stimulates receptor phosphorylation. If a second E binds, to form an E-R*R*-E complex, then intermolecular phosphorylation of E will be stimulated, and the E*-R*R*-E* complex will have high kinase activity. Phosphorylated E* may be released into the cytosol, to phosphorylate more receptors. This would provide a mechanism for hysteresis in signaling.
FIGURE 2
FIGURE 2. Positive and negative feedback effects due to SFK binding to monomeric receptors
(a) Reactions and equations describing the conformation states of the SFK and monomeric receptor phosphorylation. These reactions are solved in Appendix 1. (b) Fractional receptor phosphorylation (fR) as a function of the ratio of SFK and PTP activities (the control parameter for receptor phosphorylation, θR). Results are shown for different values of the equilibrium between closed and open SFK (Q), the ratio of total SFK to receptor (Et/Rt), and the product of receptor concentration and binding affinity (K3Rt). The control (red line) is for no binding of E to R*. Black lines show results where positive feedback (+) predominates. Blue lines show where negative feedback predominates (−).
FIGURE 3
FIGURE 3. Trans-phosphorylation of dimeric receptors
(a) Reactions and equations describing the interactions of open-conformation E with dimeric receptor RR. The phosphorylation/dephosphorylation and association constants are as in Fig. 2, except k4 represents receptor trans-phosphorylation within a RR*-E complex. These reactions are solved in Appendix 2. (b) Fractional receptor phosphorylation (fR) as a function of the control parameter for receptor phosphorylation (θR), for particular values of Q, Et/Rt and K3Rt. The control (red) is for monomeric receptors. Black lines show results for dimeric receptors with various values of the receptor trans-phosphorylation parameter (σ). Dimerization does not change any parameter except σ, which increases fR (red arrow). (c) Relative increase in receptor phosphorylation due to dimerization.
FIGURE 4
FIGURE 4. Trans-phosphorylation of SFK
(a) Reactions and equations describing the intermolecular phosphorylation of E. Phosphorylation of E, alone or complexed with various forms of R*, occurs with bi-molecular rate constant q1, and dephosphorylation occurs with pseudo-first order rate constant q2. q4 represents SFK trans-phosphorylation within a E-R*R*-E complex. These reactions are solved in Appendix 3. (b) Fractional SFK phosphorylation (fE) as a function of the control parameter for receptor phosphorylation (θR), for particular values of the phosphorylation-induced increase in SFK activity (ϕ) and the control parameter for SFK phosphorylation (θE). The control (red) is for monomeric receptors. Blue lines show results for dimeric receptors with various values of the SFK trans-phosphorylation parameter (ξ). Dimerization does not change any parameter except σ, which increases fE (red arrow). (c) Fractional receptor phosphorylation. Same parameters as in (b). (d) Relative increase in receptor phosphorylation due to dimerization. These graphs were constructed by interpolation of the data in (c).
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References

    1. Tamir I, Cambier JC. Antigen receptor signaling: integration of protein tyrosine kinase functions. Oncogene. 1998;17:1353–1364. - PubMed
    1. Sigalov A. Multi-chain immune recognition receptors: spatial organization and signal transduction. Semin. Immunol. 2005;17:51–64. - PubMed
    1. Germain RN. T-cell signaling: the importance of receptor clustering. Curr. Biol. 1997;7:R640–R644. - PubMed
    1. Veillette A, Latour S, Davidson D. Negative regulation of immunoreceptor signaling. Annu. Rev. Immuno. 2002;20:669–707. - PubMed
    1. Fuller GL, Williams JA, Tomlinson MG, Eble JA, Hanna SL, Pohlmann S, Suzuki-Inoue K, Ozaki Y, Watson SP, Pearce AC. The C-type lectin receptors CLEC-2 and Dectin-1, but not DC-SIGN, signal via a novel YXXL-dependent signaling cascade. J. Biol. Chem. 2007;282:12397–12409. - PMC - PubMed

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