ArticleThe Journal of biological chemistry2014
Glycosylation at Asn211 regulates the activation state of the discoidin domain receptor 1 (DDR1).
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 38 citations in OpenAlex.
- Transmembrane association of DDR1 and DDR2 mediated by Leucine zipper motifs.Magnetic resonance letters · 2025Article
- Blockade of DDR1/PYK2/ERK signaling suggesting SH2 superbinder as a novel autophagy inhibitor for pancreatic cancer.Cell death & disease · 2023Article
- Review
- Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease.Frontiers in pharmacology · 2022Review
- Expression and subcellular localization of Discoidin Domain Receptor 1 (DDR1) define prostate cancer aggressiveness.Cancer cell international · 2021Article
- Quantitative phosphoproteomics uncovers dysregulated kinase networks in Alzheimer's disease.Nature aging · 2021Article
- Glycosylation and raft endocytosis in cancer.Cancer metastasis reviews · 2020Review
- DDR1 autophosphorylation is a result of aggregation into dense clusters.Scientific reports · 2019Article
- Discoidin domain receptors: Micro insights into macro assemblies.Biochimica et biophysica acta. Molecular cell research · 2019Review
- Article
- The Extracellular Matrix Receptor Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus.Journal of the American Society of Nephrology : JASN · 2019Article
- Clustering, Spatial Distribution, and Phosphorylation of Discoidin Domain Receptors 1 and 2 in Response to Soluble Collagen I.Journal of molecular biology · 2019Article
- Spatial localisation of Discoidin Domain Receptor 2 (DDR2) signalling is dependent on its collagen binding and kinase activity.Biochemical and biophysical research communications · 2018Article
- Status Report on the High-Throughput Characterization of Complex Intact O-Glycopeptide Mixtures.Journal of the American Society for Mass Spectrometry · 2018Article
- Mechanical signaling through the discoidin domain receptor 1 plays a central role in tissue fibrosis.Cell adhesion & migration · 2018Review
- Signaling by discoidin domain receptor 1 in cancer metastasis.Cell adhesion & migration · 2018Review
- Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery.Drug discovery today · 2015Review
- Discoidin domain receptors: a proteomic portrait.Cellular and molecular life sciences : CMLS · 2014Review
- Normal activation of discoidin domain receptor 1 mutants with disulfide cross-links, insertions, or deletions in the extracellular juxtamembrane region: mechanistic implications.The Journal of biological chemistry · 2014Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Discoidin domain receptor 1 (DDR1) belongs to a unique family of receptor tyrosine kinases that signal in response to collagens. DDR1 undergoes autophosphorylation in response to collagen binding with a slow and sustained kinetics that is unique among members of the receptor tyrosine kinase family. DDR1 dimerization precedes receptor activation suggesting a structural inhibitory mechanism to prevent unwarranted phosphorylation. However, the mechanism(s) that maintains the autoinhibitory state of the DDR1 dimers is unknown. Here, we report that N-glycosylation at the Asn(211) residue plays a unique role in the control of DDR1 dimerization and autophosphorylation. Using site-directed mutagenesis, we found that mutations that disrupt the conserved (211)NDS N-glycosylation motif, but not other N-glycosylation sites (Asn(260), Asn(371), and Asn(394)), result in collagen I-independent constitutive phosphorylation. Mass spectrometry revealed that the N211Q mutant undergoes phosphorylation at Tyr(484), Tyr(520), Tyr(792), and Tyr(797). The N211Q traffics to the cell surface, and its ectodomain displays collagen I binding with an affinity similar to that of the wild-type DDR1 ectodomain. However, unlike the wild-type receptor, the N211Q mutant exhibits enhanced receptor dimerization and sustained activation upon ligand withdrawal. Taken together, these data suggest that N-glycosylation at the highly conserved (211)NDS motif evolved to act as a negative repressor of DDR1 phosphorylation in the absence of ligand. The presence of glycan moieties at that site may help to lock the collagen-binding domain in the inactive state and prevent unwarranted signaling by receptor dimers. These studies provide a novel insight into the structural mechanisms that regulate DDR activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.