Normal Activation of Discoidin Domain Receptor 1 Mutants with Disulfide Cross-links, Insertions, or Deletions in the Extracellular Juxtamembrane Region

Xu, Haisheng; Abe, Takemoto; Liu, Justin Kin Ho; Zalivina, Irina; Hohenester, Erhard; Leitinger, Birgit

doi:10.1074/jbc.m113.536144

Cited by 33 publications

(41 citation statements)

References 51 publications

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“…However, how collagen binding to the extracellular DS domains induces intracellular kinase activation is not known. In contrast to most other RTKs, which are thought to be present as monomers in the absence of ligand and to dimerise upon ligand binding [92], the DDRs are constitutive dimers [93][94][95]. Therefore, the model of ligand-induced receptor dimerisation does not apply to the DDRs.…”

Section: Ddr Signallingmentioning

confidence: 99%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

Self Cite

160

109

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Section: Ddr Signallingmentioning

confidence: 99%

Extracellular matrix component signaling in cancer

Multhaupt

Leitinger

Gullberg

et al. 2016

Advanced Drug Delivery Reviews

Self Cite

160

109

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“…An alternative activation mechanism would be higher‐order receptor clustering , which does not preclude the presence of constitutive GPVI dimers in non‐activated platelets. Clustering has been demonstrated for many classes of receptor, including G‐protein‐coupled receptors , adhesion receptors such as platelet integrin α IIb β 3 , platelet C‐type lectin‐like receptor 2 , and, notably, discoidin domain receptor 1, a constitutively dimeric tyrosine kinase receptor for collagen .…”

Section: Introductionmentioning

confidence: 99%

Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets

Poulter

Pollitt

Owen

et al. 2017

Journal of Thrombosis and Haemostasis

100

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Essentials Dimeric high‐affinity collagen receptor glycoprotein VI (GPVI) is present on resting platelets.Spatio‐temporal organization of platelet GPVI‐dimers was evaluated using advanced microscopy.Upon platelet adhesion to collagenous substrates, GPVI‐dimers coalesce to form clusters.Clustering of GPVI‐dimers may increase avidity and facilitate platelet activation SummaryBackgroundPlatelet glycoprotein VI (GPVI) binding to subendothelial collagen exposed upon blood vessel injury initiates thrombus formation. Dimeric GPVI has high affinity for collagen, and occurs constitutively on resting platelets.ObjectiveTo identify higher‐order oligomerization (clustering) of pre‐existing GPVI dimers upon interaction with collagen as a mechanism to initiate GPVI‐mediated signaling.Methods GPVI was located by use of fluorophore‐conjugated GPVI dimer‐specific Fab (antigen‐binding fragment). The tested substrates include Horm collagen I fibers, soluble collagen III, GPVI‐specific collagen peptides, and fibrinogen. GPVI dimer clusters on the platelet surface interacting with these substrates were visualized with complementary imaging techniques: total internal reflection fluorescence microscopy to monitor real‐time interactions, and direct stochastic optical reconstruction microscopy (dSTORM), providing relative quantification of GPVI cluster size and density. Confocal microscopy was used to locate GPVI dimer clusters, glycoprotein Ib, integrin α2β1, and phosphotyrosine.ResultsUpon platelet adhesion to all collagenous substrates, GPVI dimers coalesced to form clusters; notably clusters formed along the fibers of Horm collagen. dSTORM revealed that GPVI density within clusters depended on the substrate, collagen III being the most effective. Clusters on fibrinogen‐adhered platelets were much smaller and more numerous; whether these are pre‐existing oligomers of GPVI dimers or fibrinogen‐induced is not clear. Some GPVI dimer clusters colocalized with areas of phosphotyrosine, indicative of signaling activity. Integrin α2β1 was localized to collagen fibers close to GPVI dimer clusters. GPVI clustering depends on a dynamic actin cytoskeleton.ConclusionsPlatelet adhesion to collagen induces GPVI dimer clustering. GPVI clustering increases both avidity for collagen and the proximity of GPVI‐associated signaling molecules, which may be crucial for the initiation and persistence of signaling.

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“…It has previously been suggested that stimulating DDR1 with its ligand, collagen, causes aggregation [32][33][34]. Here, we label DDR1 with a SNAP-tag that has been stochastically linked to Alexa488 or Alexa546.…”

Section: Resultsmentioning

confidence: 99%

Mapping Molecular Function to Biological Nanostructure: Combining Structured Illumination Microscopy with Fluorescence Lifetime Imaging (SIM + FLIM)

et al. 2017

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Abstract:We present a new microscope integrating super-resolved imaging using structured illumination microscopy (SIM) with wide-field optically sectioned fluorescence lifetime imaging (FLIM) to provide optical mapping of molecular function and its correlation with biological nanostructure below the conventional diffraction limit. We illustrate this SIM + FLIM capability to map FRET readouts applied to the aggregation of discoidin domain receptor 1 (DDR1) in Cos 7 cells following ligand stimulation and to the compaction of DNA during the cell cycle.

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Normal Activation of Discoidin Domain Receptor 1 Mutants with Disulfide Cross-links, Insertions, or Deletions in the Extracellular Juxtamembrane Region

Cited by 33 publications

References 51 publications

Extracellular matrix component signaling in cancer

Extracellular matrix component signaling in cancer

Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets

Mapping Molecular Function to Biological Nanostructure: Combining Structured Illumination Microscopy with Fluorescence Lifetime Imaging (SIM + FLIM)

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