The overarching goal of the TGF-BTB (Transforming Growth Factor – Bench To Bedside) project is to unravel the distinct roles played by TGF-β isoforms, a group of growth factor molecules that, much like hormones, circulate within our body and engage specific cell surface receptors, thereby initiating signalling pathways that regulate a multitude of critical physiological processes. TGF-βs exert profound influence on cell proliferation, wound healing, cancer progression, and immune responses. Elevated TGF-β signalling often manifests in conditions such as cancer, fibrotic diseases, and chronic inflammation. Following cardiac infarction or other forms of cardiac injury, TGF-β overexpression can lead to life-altering complications.
A central focus of TGF-BTB is the exploration of the enigmatic co-receptor, Betaglycan. Betaglycan is referred to as a "co-receptor" because TGF-β can bind to it without triggering signal transmission. However, it has been demonstrated that Betaglycan enhances TGF-β activity by presenting it to the signaling receptors. This enhancement is particularly crucial for one isoform, TGF-β2, as its natural binding affinity to the signaling receptors is insufficient for signaling without Betaglycan's presence. To gain deeper insights into the mechanisms underpinning Betaglycan's signaling potentiation and to appreciate the significance of preserving three distinct TGF-β isoforms and their selective inhibition, TGF-BTB has established the following objectives:
• To attain a comprehensive molecular understanding of the TGF-β:Betaglycan complex.
• To observe TGF-β:Betaglycan complex formation and the transfer of the ligand to the signalling receptor, both in vitro and in vivo.
• To design a peptide-based inhibitor capable of effectively blocking TGF-β signalling, suitable for functional studies and with potential clinical applications.
Throughout the course of this project, we have gained a comprehensive understanding of the interaction between Betaglycan and TGF-β Growth Factors. This knowledge has allowed us to elucidate how Betaglycan can bind to TGF-β while still providing space for partial binding of the signalling receptor, enabling the seamless transfer of TGF-β. The structural insights obtained have clarified the mechanisms underlying ligand specificity, shedding light on which isoforms are most susceptible to the loss of Betaglycan subdomains.
Furthermore, during the project's duration, we embarked on the endeavor to design peptide-based inhibitors tailored for the TGF-β signaling pathway. These inhibitors were intended to complement checkpoint anticancer therapy, enhancing its efficacy, and addressing persistent inflammatory conditions associated with lung remodeling in COPD or asthma. After multiple iterations, our designed peptide-based inhibitors have proven to be effective and highly specific for the TGF-β pathway.
