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Review
. 2020 Dec 25;295(52):18494-18507.
doi: 10.1074/jbc.REV120.015190. Epub 2020 Oct 29.

Ligand bias in receptor tyrosine kinase signaling

Kelly Karl  1 , Michael D Paul  1 , Elena B Pasquale  2 , Kalina Hristova  3
Affiliations
Review

Ligand bias in receptor tyrosine kinase signaling

Kelly Karl et al. J Biol Chem. .

Abstract

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein-coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.

Keywords: Receptor tyrosine kinase (RTK); bias coefficient; bias plot; cell signaling; dimer stability; dimerization; ligand bias; ligand functional selectivity; mathematical modeling; phosphotyrosine signaling; protein conformation; receptor; receptor tyrosine kinase; signaling; thermodynamics.

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Conflict of interest statement

Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1
Figure 1
Ligand bias can lead to fundamentally different receptor signaling outcomes. A schematic illustrates different cases in which two ligands induce dimerization of a RTK and downstream signaling. The stars represent two signaling responses: response A in green and response B in red. The size of the stars represents the efficiency of a response (i.e. a combination of the potency of the ligand and the magnitude (or efficacy) of the response) (Table 1). In case i, ligand 1 induces both responses more efficiently than ligand 2, but the two responses are equally increased with ligand 1, and therefore there is no bias. In case ii, response B is more efficient for both ligands, and in addition ligand 1 induces both responses more efficiently, but there is no bias in the responses induced by the two ligands. There is bias only in case iii, where only response B is more efficiently induced by ligand 1 compared with ligand 2, and thus ligand 1 is biased toward response B. EC, extracellular region; TM, transmembrane helix; IC, intracellular region.
Figure 2
Figure 2
Dose-response curves and bias plots for ligand bias assessment.A, schematic illustrating the two ligand-induced EphA2 signaling responses analyzed and dose-response curves for two peptide ligands, YSPK and YSK, that activate the EphA2 RTK in PC3 prostate cancer cells. The two responses measured are autophosphorylation on tyrosine 588 (pY588, which is normalized to total EphA2 levels) and inhibition of AKT phosphorylation (pAKT). The 100 nm concentration is highlighted in the graphs to emphasize the different potency of the two ligands. B, bias plot comparing the two responses for the two ligands. The color coding for the two responses (green and red) and the two ligands (blue and orange) are the same as in Fig. 1.
Figure 3
Figure 3
Predictions of responses for dimeric ligands based on the RTK operational model.A, schematic and thermodynamic cycle describing VEGFA binding to VEGFR2 and VEGFR2 dimerization. B, definitions of the three principal dissociation constants. C, definition of the other dissociation constants in terms of the three principal ones. D, predicted orange curve: abundance of VEGFR2 dimers bound to VEGFA [DL] as a function of VEGFA (ligand 1) concentration. Predicted blue curve, abundance of VEGFR2 dimers [DL] bound to a hypothetical ligand 2 as a function of ligand 2 concentration. E, measured dissociation constant values for VEGFA from Ref. and assigned dissociation constant values for the hypothetical ligand 2, which binds with 10-fold higher affinity than ligand 1 to the VEGFR2 dimer. F, dose-response curves predicted using Equation 24 based on the values shown in G. G, values of Kresp for responses A or B and for ligands 1 or 2 that were used to simulate the cases of bias and no bias in F. In all cases, [Rt] = 500 receptors/µm2. H, bias plots calculated from the predictions in F.
Figure 4
Figure 4
Model describing the binding of a monomeric ligand to an RTK and RTK dimerization.A, thermodynamic cycle. B, definitions of the four principal equilibrium dissociation constants. C, definitions of the other equilibrium constants in terms of the four principal ones.
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