Discoidin domain receptor 1 is activated independently of beta(1) integrin.
Various types of collagen have been identified as potential ligands for the two mammalian discoidin domain receptor (DDR) tyrosine kinases, DDR1 and DDR2. It is presently unclear whether collagen-induced DDR receptor activation, which occurs with very slow kinetics, involves additional proteins with kinase activity or membrane-anchored proteins serving as coreceptors. In particular, the role of the collagen-binding integrins alpha(1)beta(1) or alpha(2)beta(1) in the DDR activation process is undefined. Here, we provide three lines of evidence suggesting that DDR1 signaling is distinct from integrin activation. First we demonstrate that the enzymatic activity of DDR1 is essential for receptor tyrosine phosphorylation. Collagen-induced DDR receptor autophosphorylation can be blocked either by a dominant negative mutant or by a preparation of recombinant extracellular domain. Second, we show DDR1 signals independent of the epidermal growth factor (EGF) receptor. In cells that endogenously express both DDR1 and the EGF receptor, stimulation with EGF does not induce DDR activation. Third, we detected full DDR1 activation after collagen stimulation in cells that have been treated with blocking antibodies for alpha(2)beta(1) integrin or in cells with a targeted deletion of the beta(1) integrin gene. Finally, we show that overexpression of dominant negative DDR1 in the myoblast cell line C2C12 blocks cellular differentiation and the formation of myofibers.
Vogel
W
W
Programme in Molecular Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. W.Vogel@em.uni-frankfurt.de
Brakebusch
C
C
Fässler
R
R
Alves
F
F
Ruggiero
F
F
Pawson
T
T
D016475:3T3 Cells; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000166:cytology; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D011975:Receptors, Mitogen / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured
D019012:Integrin beta1; D016023:Integrins; D011975:Receptors, Mitogen; D011994:Recombinant Proteins; D003094:Collagen; D000070818:Discoidin Domain Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases