Discoidin Domain Receptor Signaling in Cancer Biology

Discoidin domain receptors (DDRs) are unique receptor tyrosine kinases that bind to collagen in the extracellular matrix and exhibit slow but sustained activation kinetics. Two family members, DDR1 and DDR2, respond to distinct collagen types and initiate intracellular cascades that regulate cell proliferation, survival, motility and differentiation. In cancer biology, aberrant DDR signalling contributes to tumour progression at multiple levels. By engaging pathways such as MAPK, PI3K–AKT, Hippo–YAP and HIF-1α, DDRs modulate the tumour microenvironment, promote angiogenesis, support epithelial–mesenchymal transition and facilitate metastatic dissemination. Crosstalk with integrins and mechanotransduction sensors further integrates DDR activity with matrix stiffness and fluid shear forces, linking physical cues to gene expression programmes that underlie tumour growth and spread. The sustained nature of DDR activation makes these receptors attractive therapeutic targets, and selective inhibitors are under investigation to disrupt collagen-driven tumour biology and overcome therapeutic resistance.

Research from Nature Portfolio

Recent studies have revealed an unexpected role for DDR1 as a direct sensor of mechanical force in vascular cells. Under shear stress, conformational changes in the DDR1 ectodomain expose a critical cysteine residue, driving receptor oligomerisation and the formation of liquid-like condensates. These condensates co-assemble with adaptor proteins to trigger nuclear translocation of YAP, a transcriptional co-activator central to Hippo pathway regulation. This mechanotransduction mechanism links collagen engagement and blood flow to pro-atherogenic and pro-angiogenic programmes, highlighting how DDR1 integrates physical and biochemical signals within the tumour vasculature.

Discoidin Domain Receptor Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in discoidin domain receptor signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Receptor tyrosine kinase (RTK): A cell surface enzyme that phosphorylates tyrosine residues on target proteins in response to extracellular ligands.

Extracellular matrix (ECM): A network of proteins and polysaccharides surrounding cells, providing structural support and regulating signalling.

Mechanotransduction: The process by which cells convert mechanical stimuli into biochemical signals.

YAP: Yes-associated protein, a transcriptional co-activator regulated by the Hippo pathway, involved in cell proliferation and survival.

Hippo pathway: A signalling cascade that controls organ size and tumour growth by regulating YAP activity.

Epithelial–mesenchymal transition (EMT): A cellular programme in which epithelial cells acquire migratory and invasive mesenchymal properties.

Ubiquitination: A post-translational modification in which ubiquitin molecules are attached to a protein, often marking it for degradation.

References

1. Endothelial discoidin domain receptor 1 senses flow to modulate YAP activation. Nature Communications (2023).
2. DDR1 Drives Malignant Progression of Gastric Cancer by Suppressing HIF‐1α Ubiquitination and Degradation. Advanced Science (2024).
3. DDR1 promotes metastasis of cervical cancer and downstream phosphorylation signal via binding GRB2. Cell Death & Disease (2024).
4. Inhibition of DDR1‐BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer. EMBO Molecular Medicine (2018).
5. Discoidin Domain Receptors Promote α1β1- and α2β1-Integrin Mediated Cell Adhesion to Collagen by Enhancing Integrin Activation. PLOS ONE (2012).
6. Discoidin Domain Receptors: Unique Receptor Tyrosine Kinases in Collagen-mediated Signaling*. Journal of Biological Chemistry (2013).
7. Collagen binding specificity of the discoidin domain receptors: Binding sites on collagens II and III and molecular determinants for collagen IV recognition by DDR1. Matrix Biology (2010).
8. Discovery of a Potent and Selective DDR1 Receptor Tyrosine Kinase Inhibitor. ACS Chemical Biology (2013).
9. Molecular Analysis of Collagen Binding by the Human Discoidin Domain Receptors, DDR1 and DDR2 IDENTIFICATION OF COLLAGEN BINDING SITES IN DDR2*. Journal of Biological Chemistry (2003).