TGFBR1: Core component of a multifunctional signaling pathway


In this image of the month, we highlight TGFBR1, a central component of the TGF-beta signaling pathway. Signaling pathways are the way cells communicate with each other and with their microenvironment, and their proper function is crucial for the coordination of cellular, tissue and organ functions throughout life.

TGF-beta signaling is a highly conserved pathway, which under physiological conditions, plays essential roles during embryonic development and adult tissue homeostasis (Morikawa et al, 2016). The tight regulation of the pathway at different levels and by different mechanisms is important in order to ensure its proper function. Mutations that occur in different components of the TGF-beta pathway and malfunction of the various regulatory mechanisms that lead to weaker or (more often) enhanced signaling, are associated with the onset or alternatively the later stages of various diseases including fibrotic disorders and cancer. Interestingly, the role of TGF-beta signaling in cancer is actually dual, acting as a tumor suppressor in early stages of tumorigenesis and promoting tumor cell invasion and metastasis at later stages (David and Massague, 2018).

TGFBR1 is a plasma membrane localized type I TGF-beta serine/threonine kinase receptor, which is expressed in all cell types of the human body. In the presence of the TGF-beta ligand, TGFBR1 forms a complex with TGFBR2, and is responsible for transducing the TGF-beta signal from the cell surface to the cytoplasm by phosphorylating the downstream mediators of the pathway (mainly the SMAD proteins). This will eventually lead to the regulation of genes related to a broad spectrum of cellular processes, such as cell proliferation, differentiation, apoptosis and cell motility (Tzavlaki and Moustakas, 2020).

As expected, the availability/activity of TGFBR1 is fine-tuned by a variety of regulatory mechanisms (e.g. co-receptors, phosphatases). The TGFBR1 gene is not so often found mutated in cancers, but perturbations in the function of its regulatory mechanisms lead to aberrant signaling, which in turn contributes to cancer progression.

Small molecule inhibitors that target the kinase activity of TGFBR1 have been developed and tested in pre-clinical models giving some promising results. However, including such an inhibitor in cancer treatment schemes, has been a big challenge in clinical trials, partly because of the multifunctional nature of TGF-beta signaling and its importance to the maintenance of tissue homeostasis (Teixeira et al, 2020).