DDR1

DDR1 is a collagen receptor kinase that couples engagement of ECM collagen to cytoskeletal and mechanotransduction responses in cancer cells. In dedifferentiated mesenchymal melanoma cells, DDR1 together with DDR2 is activated and drives actomyosin cytoskeleton reorganization and the YAP mechanotransduction pathway in response to ECM stiffness; dual DDR inhibition abrogates this mechano-induced behavior and associated drug resistance, while forced expression of the receptors in melanocytic cells confers mechanical responsiveness and a less differentiated phenotype [PMID:bio_10.1101_2024.08.26.609700]. DDR1 can be selectively engaged in intact cells by type II kinase inhibitors in a manner not always recapitulated in cell-free biochemical assays, indicating that cellular context shapes inhibitor binding [PMID:bio_10.1101_2025.10.09.681452]. Beyond these collagen-driven, mechanotransduction, and inhibitor-engagement findings, no further molecular dissection of DDR1 signaling has been characterized in the available corpus.

1. 2024 Medium

   Established that DDR1, as a collagen receptor, is an upstream driver of ECM-stiffness-dependent mechanotransduction in dedifferentiated cancer cells rather than a passive adhesion receptor.

   Evidence Pharmacological DDR1/2 inhibition, forced expression in melanocytic cells, collagen-stiffness assays with YAP and phenotypic readouts in melanoma

   PMID:bio_10.1101_2024.08.26.609700

   Open questions at the time

   • Does not separate DDR1 from DDR2 contributions
   • Kinase-dependence and direct molecular link to YAP activation not dissected
   • Preprint, single lab, not peer-reviewed
2. 2025 Low

   Linked DDR1-collagen engagement to formation of collagen-track membrane structures, proposing a cell-cell communication route that promotes invasion.

   Evidence 3D matrix deposition assays in vitro and in vivo with and without DDR1-ECM interaction, plus functional transfer assays in breast cancer

   PMID:bio_10.1101_2025.01.25.634857

   Open questions at the time

   • No direct mutagenesis or molecular dissection of DDR1's role
   • Single preprint, single lab
   • Mechanism connecting DDR1 signaling to track formation undefined
3. 2025 Low

   Showed that cellular context governs DDR1 inhibitor binding, since type II inhibitors engage DDR1 in intact cells but not always in cell-free assays.

   Evidence NanoBRET cellular target engagement assay compared against cell-free biochemical kinase panel for TPKI-39 and related inhibitors

   PMID:bio_10.1101_2025.10.09.681452

   Open questions at the time

   • Characterizes inhibitor engagement, not endogenous DDR1 mechanism
   • Structural basis of context-dependent binding unknown
   • Single preprint, single lab

• How DDR1 kinase activity mechanistically couples collagen binding to YAP activation, cytoskeletal remodeling, and collagen-track formation, and whether these roles are kinase-dependent, remains unresolved.
• No direct DDR1 substrate or signaling intermediate identified
• DDR1-specific (vs DDR2) contributions not isolated
• No structural or biochemical reconstitution of collagen-induced signaling in the corpus