The discoidin domain receptor tyrosine kinases are activated by collagen.
Two mammalian receptor tyrosine kinases (DDR1 and DDR2) have extracellular domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation. Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen and occurs over an extended period of time. Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain, whose presence is controlled by alternative splicing. Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression. These results suggest that the discoidin-related DDR tyrosine kinases are novel collagen receptors with the potential to control cellular responses to the extracellular matrix.
Vogel
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W
Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Gish
G D
GD
Alves
F
F
Pawson
T
T
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001672:Biocompatible Materials; D001943:Breast Neoplasms; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry; D003094:Collagen / Q000378:metabolism* / Q000494:pharmacology; D017364:Collagenases / Q000096:biosynthesis / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D005354:Fibrosarcoma; D006358:Hot Temperature; D006801:Humans; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D007797:Laminin; D008024:Ligands; D020781:Matrix Metalloproteinase 1; D051379:Mice; D008969:Molecular Sequence Data; D010434:Pepsin A / Q000494:pharmacology; D010766:Phosphorylation; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D011509:Proteoglycans; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D011975:Receptors, Mitogen / Q000737:chemistry* / Q000378:metabolism*; D013710:Tendons / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D014443:Tyrosine / Q000378:metabolism
D001672:Biocompatible Materials; D002241:Carbohydrates; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins; D007797:Laminin; D008024:Ligands; D011509:Proteoglycans; D011975:Receptors, Mitogen; C059485:matrigel; D014443:Tyrosine; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D010434:Pepsin A; D017364:Collagenases; D020781:Matrix Metalloproteinase 1