Various types of collagen have been identified as potential ligands for the
two mammalian discoidin domain receptor (DDR) tyrosine kinases, DDR1 and D
DR2, It is presently unclear whether collagen-induced DDR receptor activati
on, which occurs with very slow kinetics, involves additional proteins with
kinase activity or membrane-anchored proteins serving as coreceptors. In p
articular, the role of the collagen-binding integrins alpha(1)beta(1) or al
pha(2)beta(1) in the DDR activation process is undefined. Here, we provide
three lines of evidence suggesting that DDR1 signaling is distinct from int
egrin activation. First we demonstrate that the enzymatic activity of DDR1
is essential for receptor tyrosine phosphorylation, Collagen-induced DDR re
ceptor autophosphorylation can be blocked either by a dominant negative mut
ant or by a preparation of recombinant extracellular domain, Second, we sho
w DDR1 signals independent of the epidermal growth factor (EGF) receptor. I
n cells that endogenously express both DDR1 and the EGF receptor, stimulati
on with EGF does not induce DDR activation. Third, we detected full DDR1 ac
tivation after collagen stimulation in cells that have been treated with bl
ocking 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.