Receptor binding competition: A paradigm for regulating TGF-β family action

• Published in: Cytokine & growth factor reviews 2021-02, Vol.57, p.39-54
• Main Authors: Martinez-Hackert, Erik, Sundan, Anders, Holien, Toril
• Format: Article
• Language: English
• Subjects: Activin; BMP; Competition; Signaling; SMAD; TGF-β
• ISSN: 1359-6101; 1879-0305
• DOI: 10.1016/j.cytogfr.2020.09.003

[Display omitted] •Ligand-receptor binding-competition is a key feature of the TGF-β family.•Ligands can function as agonists or antagonists depending on the cellular context.•Ligand-receptor binding-competition enables cells to read and process complex information encoded in ligand combinations.•Ligand-receptor binding-competition enables cells to exhibit input-output plasticity.•The functional importance of binding-competition is stressed by its potential roles in human physiology, disease, and therapy. The transforming growth factor (TGF)-β family is a group of structurally related, multifunctional growth factors, or ligands that are crucially involved in the development, regulation, and maintenance of animal tissues. In humans, the family counts over 33 members. These secreted ligands typically form multimeric complexes with two type I and two type II receptors to activate one of two distinct signal transduction branches. A striking feature of the family is its promiscuity, i.e., many ligands bind the same receptors and compete with each other for binding to these receptors. Although several explanations for this feature have been considered, its functional significance has remained puzzling. However, several recent reports have promoted the idea that ligand-receptor binding promiscuity and competition are critical features of the TGF-β family that provide an essential regulating function. Namely, they allow a cell to read and process multi-ligand inputs. This capability may be necessary for producing subtle, distinctive, or adaptive responses and, possibly, for facilitating developmental plasticity. Here, we review the molecular basis for ligand competition, with emphasis on molecular structures and binding affinities. We give an overview of methods that were used to establish experimentally ligand competition. Finally, we discuss how the concept of ligand competition may be fundamentally tied to human physiology, disease, and therapy.