Abstract
The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.
Highlights
The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders
We showed that collagen binding results in redistribution of DDR1 on the cell surface into a more compact structure, and that this collagen-induced clustering can be prevented by a blocking monoclonal antibody[10]
We had earlier concluded that the monoclonal antibody (mAb) interferes with DDR1 activation allosterically because it binds to an extracellular epitope on the discoidin-like domain and does not interfere with DDR1 ligand binding, as assessed by solid phase binding assay of recombinant DDR1 extracellular region to a collagen-mimetic triple-helical peptide[14]
Summary
The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression of a wide range of human disorders. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. We demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics. The molecular events underpinning the process of ligand-induced kinase activation have been revealed for a number of well-studied RTKs, including epidermal growth factor (EGF) and insulin receptors[1,2]. Within 5 minutes of collagen binding, DDR1 redistributes into morphologically distinct clusters that contain unphosphorylated DDR1. We have found a simple explanation for the unusually slow DDR1 activation kinetics
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