Thrombospondin-1 (TSP-1) – latent transforming growth factor beta (TGF-beta) interaction (TSP-1 – latent TGF-beta interaction)

Thrombospondin-1 (TSP-1) is a large, multifunctional matricellular glycoprotein that plays a pivotal role in regulating cellular phenotype and the structure of the extracellular matrix. One of its most significant functions is the non-proteolytic activation of latent transforming growth factor-beta (TGF-beta), a potent cytokine involved in fibrosis, immune suppression, and tissue remodeling (Murphy-Ullrich & Suto, 2018). TSP-1 facilitates this activation by binding to the Latency-Associated Peptide (LAP) of the latent TGF-beta complex, specifically through its type 1 repeat (TSR) domains, which triggers a conformational change that releases active TGF-beta (Sweetwyne & Murphy-Ullrich, 2012). This interaction is a major driver of pathological TGF-beta signaling in various diseases, including chronic kidney disease, pulmonary fibrosis, and certain cancers where TGF-beta promotes epithelial-mesenchymal transition and immune evasion (Lu et al., 2011). Because global inhibition of TGF-beta can lead to severe side effects like systemic inflammation and autoimmunity, targeting the specific TSP-1–latent TGF-beta interaction offers a more localized and selective therapeutic approach. Experimental inhibitors, such as the LSKL peptide and small molecules like SRW101, have demonstrated efficacy in preclinical models by preventing the formation of the TSP-1/LAP complex and subsequent TGF-beta release (Kondou et al., 2003).

Other names

TSP-1/TGF-beta activation complexThrombospondin-1/LAP interactionTSP1-mediated TGF-beta activationTSP1-TGFB1 interaction

Competitive inhibition of the protein-protein interaction between the KRFK motif of Thrombospondin-1 and the LSKL sequence of the Latency-Associated Peptide (LAP), preventing the conformational release of active TGF-beta (Murphy-Ullrich & Suto, 2018).