Thrombospondin-1 (TSP-1) (TSP-1)

Thrombospondin-1 (TSP-1) is a large, homotrimeric matricellular glycoprotein that plays a pivotal role in regulating cell-matrix interactions and inhibiting angiogenesis (UniProt P35442). A highly specific functional domain within its type 1 repeats (TSRs) is the KRFK (Lys-Arg-Phe-Lys) sequence, which is uniquely responsible for the non-proteolytic activation of latent Transforming Growth Factor-beta (TGF-beta) (Ribeiro et al., 1999, PubMed: 10409623). This activation occurs when the KRFK motif binds to the LSKL (Leu-Ser-Lys-Leu) sequence on the Latency Associated Peptide (LAP) of TGF-beta, inducing a conformational change that releases the active cytokine into the extracellular environment (Murphy-Ullrich and Poczatek, 2000, PubMed: 10792391). Pathologically, this TSP-1-mediated activation is a primary driver of tissue fibrosis in organs such as the kidneys and lungs, and it facilitates tumor progression by promoting an immunosuppressive microenvironment (Lu et al., 2017, PubMed: 28450770). Therapeutic strategies, such as the LSKL inhibitory peptide, specifically target this KRFK-mediated interaction to prevent TGF-beta activation without the adverse effects associated with global TGF-beta signaling blockade (Kondou et al., 2003, PubMed: 12631555). Consequently, the TSP-1 KRFK sequence is a significant therapeutic target for treating chronic fibroproliferative diseases and enhancing anti-tumor immunity.

Other names

THBS1TSP1Thrombospondin-1p180Glycoprotein GTSP-1 KRFK motif

Competitive inhibition of the interaction between the TSP-1 KRFK sequence and the latent TGF-beta complex, preventing the release of active TGF-beta.