Homeodomain-interacting protein kinase 2-Mothers against decapentaplegic homolog 3 protein-protein interface (HIPK2-Smad3 interface)

The Homeodomain-interacting protein kinase 2 (HIPK2)-Mothers against decapentaplegic homolog 3 (Smad3) protein-protein interface is a critical regulatory node in the Transforming Growth Factor-beta (TGF-beta) signaling pathway. HIPK2 acts as a scaffold and kinase that physically interacts with Smad3 to enhance its transcriptional activity, particularly driving the expression of pro-fibrotic genes. This interaction is a major contributor to the progression of renal fibrosis and the epithelial-to-mesenchymal transition (EMT) in chronic diseases such as diabetic nephropathy and HIV-associated nephropathy. By specifically targeting the physical interface between HIPK2 and Smad3, therapeutic strategies aim to selectively inhibit pathological TGF-beta signaling while sparing homeostatic functions, such as HIPK2-mediated p53 activation for tumor suppression. Experimental small molecules like BT173 have been developed to allosterically disrupt this interaction, demonstrating the ability to reduce fibrosis in preclinical models without the systemic toxicity typically associated with broad TGF-beta or kinase inhibition.

Other names

HIPK2-Smad3 interactionHIPK2-Smad3 complexHIPK2-Smad3 protein-protein interactionHIPK2-Smad3 PPI

Allosteric inhibition of protein-protein interaction to prevent Smad3 phosphorylation and transcriptional activation