Discoidin domain receptor tyrosine kinase (DDR) (DDR)

Discoidin domain receptors are transmembrane receptor tyrosine kinases comprised of DDR1 and DDR2, distinguished by their extracellular discoidin homology domain that binds collagens in the native triple-helical form[1][3][8]. Upon ligand binding, DDRs exhibit slow and sustained autophosphorylation and activate intracellular signaling cascades including SRC, MAPK, integrin, TGF-β, and Notch pathways[1][9]. DDRs regulate diverse biological processes such as cell adhesion, migration, proliferation, differentiation, ECM remodeling, and immune responses in both normal and pathological contexts[1][4][8][9]. Dysregulation and aberrant expression of DDRs are implicated in tumorigenesis, metastasis, fibrotic disease, arthritis, and neurodegenerative conditions[1][2][3][5][8]. DDRs are recognized as therapeutic targets, with several kinase inhibitors (e.g., nilotinib) under investigation for cancer and neurological disorders[2][5][8]. DDR1 expression serves as a biomarker in several malignancies. While DDR inhibitors show promise, broad suppression of DDR pathways presents safety challenges related to normal tissue homeostasis and potential immunomodulation[2][8].

Other names

DDR1DDR2Epithelial discoidin domain-containing receptor 1 (for DDR1)Discoidin domain receptor 1/2Receptor tyrosine kinase DDR1/DDR2

Inhibition of kinase activity by blocking ATP-binding site of DDRs, leading to: - Reduced DDR phosphorylation and downstream MAPK, SRC, and other signal pathway activation - Regulation of autophagy - Reduction in neurotoxic protein levels - Suppression of cancer cell proliferation, invasion, and remodeling