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,3
4
Departments of
* Physiology and Biophysics and
Anatomy and Neurobiology, College of Medicine, University of California, Irvine, California 92697-4560, USA; and
Centro di Biotechnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
4Correspondence: Department of Physiology and Biophysics, College of Medicine, Med Sci I D238, University of California, Irvine, CA 92697, USA. E-mail: rablab{at}uci.edu
The discoidin domain receptor (DDR1) is characterized by a discoidin I
motif in the extracellular domain, an unusually long cytoplasmic
juxtamembrane (JM) region, and a kinase domain that is 45% identical
to that of the NGF receptor, TrkA. DDR1 also has a major splice form,
which has a 37 amino acid insert in the JM region with a consensus Shc
PTB site that is lacking in the shorter receptor. One class of ligands
for the DDR receptors has recently been identified as being derived
from the collagen family, but neither native PC12 cells, which express
modest amounts of DDR1, nor transfected PC12 cells, which express much
larger amounts of DDR1, respond to this ligand. A chimeric receptor,
containing the extracellular domain of hPDGFRß fused to the
transmembrane and intracellular regions of DDR1, also fails to mediate
neuronal-like differentiation in stably transfected PC12 cells and is
only weakly autophosphorylated. However, chimeric receptors, which are
composed of combinations of intracellular regions from DDR1 and TrkA
(with the extracellular domain of hPDGFRß), in some cases
provided ligand (PDGF) -inducible receptor responses. Those with the
TrkA kinase domain and the DDR1 JM regions were able to produce
differentiation to varying degrees, whereas the opposite combination
did not. Analysis of the signaling responses of the two chimeras with
DDR1 JM sequences (with and without the insert) indicated that the
shorter sequence bound and activated FRS2 whereas the insert-containing
form activated Shc instead. Both activated PLC
through the
carboxyl-terminal tyrosine of the TrkA domain (Y785 in TrkA residue
numbering). Mutation of this site (Y
F) eliminated PLC activation
(indicating there are no other cryptic binding sites for PLC in the
DDR1 sequences) and markedly reduced the differentiative activity of
the receptor. This is in contrast to TrkA (or PDGFRß/TrkA chimeras),
where ablation of this pathway has no notable effect on PC12 cell
morphogenic responses. Thus, the activation of FRS2 and Shc (leading to
MAPK activation) is weaker in the DDR1/TrkA chimeras than in TrkA
alone, and the PLC contribution becomes essential for full response.
Nonetheless, both DDR1 JM regions contain potentially usable signaling
sites, albeit they apparently are not activated directly in DDR1 (or
DDR1 chimeras) in a ligand-dependent fashion. These findings suggest
that the DDR1 receptors do have signaling capacity but may require
additional components or altered conditions to fully activate their
kinase domains and/or sustain the activation of the JM sites.—Foehr,
E. D., Tatavos, A., Tanabe, E., Raffioni, S., Goetz, S., DiMarco,
E., De Luca, M., Bradshaw, R. A. Discoidin domain receptor 1
(DDR1) signaling in PC12 cells: activation of juxtamembrane domains in
PDGFR/DDR/TrkA chimeric receptors.
Key Words: tyrosine kinase • collagen receptor • signal transduction
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