Advances in Transforming Growth Factor-β Signaling

An article published in Experimental Biology and Medicine (Volume 246, Issue 4, February, 2021) (https://journals.sagepub.com/doi/pdf/10.1177/1535370220966296) reports a new mechanism for modulating transforming-growth factor beta (TGF-β) signaling. The study, led by Dr. Thomas Thompson, in the Department of Molecular Genetics, Biochemistry and Microbiology at the University of Cincinnati College of Medicine in Cincinnati, Ohio (USA), proposes a new mechanism for follistatin antagonism of TGF-β signaling.
Transforming growth factor beta (TGF-β) is a multifunctional cytokine produced in all white blood cells lineages. Because of its role in the immune system and stem cell biology, TGF-β has been extensively studied in cancer, auto-immune diseases, and infectious diseases. Activated TGF-β binds to specific receptors at the cell surface generating downstream signaling events that regulate differentiation, chemotaxis, proliferation, and immune cells activation. TGF-β signaling is tightly regulated by a complex network of extracellular ligands that can activate (agonists) or inhibit (antagonists) TGF-β binding to its receptor. The activity of TGF-β antagonists such as follistatin can be modulated by the extracellular matrix proteins heparin and heparin sulfate. Deciphering the molecular mechanisms that regulate TGF-β signaling is essential for understanding immune cell function and its role in various diseases.
In this study, Thompson and colleagues used surface plasmon resonance and small-angle X-ray scattering to characterize the interactions between heparin/heparin sulfate and follistatin. These studies revealed that heparin/heparin sulfate chain length alters binding kinetics for follistatin and its dimerization. Dr. Thompson said “This study helps bring into focus how antagonists of the TGF-β family are positioned on the cell surface and how this could potentially impact signaling. It also means that different cells, depending on the composition of the extracellular matrix, could impact how antagonists, such as follistatin, bind and neutralize ligands of the TGF-β family.”
Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology & Medicine, said “Dr. Thompson and colleagues provide a structural biology analysis which indicates that heparin interaction influences follistatin dimerization in a chain-length dependent manner. This localizes this TGF-β antagonist to the cell surface. The binding of follistatin and heparin unexpectedly impaired the association of mysostatin and activin A which are ligands of the TGF-β family. Together, this suggests that the cell surface availability of follistatin is inversely related to the TGF-β ligand association rate.”
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Source: Experimental Biology and Medicine