Homeodomain-interacting protein kinase 2–Mothers against decapentaplegic homolog 3 protein–protein interaction (HIPK2–Smad3 PPI)

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase that serves as a crucial regulator of the Transforming Growth Factor-beta (TGF-beta) signaling pathway (UniProt Q9H2X6). The interaction between HIPK2 and Mothers against decapentaplegic homolog 3 (Smad3) leads to the phosphorylation of Smad3, which enhances its transcriptional activity and promotes the expression of profibrotic genes (He et al., Nature Medicine, 2009). This protein-protein interaction is a key driver in the pathogenesis of chronic kidney disease and various forms of organ fibrosis, where sustained TGF-beta signaling leads to excessive extracellular matrix accumulation. Because global inhibition of TGF-beta is associated with significant toxicity due to its role in immune homeostasis and tumor suppression, targeting the specific HIPK2–Smad3 interaction offers a more selective therapeutic approach. Small molecule inhibitors, such as BT173, have been developed to disrupt this interaction, demonstrating the ability to reduce fibrosis in preclinical models by preventing the formation of the HIPK2-Smad3 complex (Nidaira et al., 2020). This target represents a promising strategy for treating progressive renal failure and potentially other fibroproliferative diseases.

Other names

HIPK2-Smad3 complexHIPK2-Smad3 signaling axisHomeodomain-interacting protein kinase 2-Smad3 interaction

Inhibition of the protein-protein interaction between HIPK2 and Smad3, preventing the phosphorylation of Smad3 at specific serine residues and subsequent activation of profibrotic genes (Nidaira et al., 2020).