Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen.
Discoidin domain receptor 2 (DDR2) is an unusual receptor tyrosine kinase in that its ligand is fibrillar collagen rather than a growth factor-like peptide. We examined signal transduction pathways of DDR2. Here we show that DDR2 is also unusual in that it requires Src activity to be maximally tyrosine-phosphorylated, and that Src activity also promotes association of DDR2 with Shc. The interaction with Shc involves a portion of Shc not previously implicated in interaction with receptor tyrosine kinases. These results identify Src kinase and the adaptor protein Shc as key signaling intermediates in DDR2 signal transduction. Furthermore, Src is required for DDR2-mediated transactivation of the matrix metalloproteinase-2 promoter. The data support a model in which Src and the DDR2 receptor cooperate in a regulated fashion to direct the phosphorylation of both the receptor and its targets.
Ikeda
Kazuo
K
Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA.
Wang
Li-Hsien
LH
Torres
Richard
R
Zhao
Hong
H
Olaso
Elvira
E
Eng
Francis J
FJ
Labrador
Pablo
P
Klein
Rudiger
R
Lovett
David
D
Yancopoulos
George D
GD
Friedman
Scott L
SL
Lin
Hsin Chieh
HC
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism*; D000070818:Discoidin Domain Receptors; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015533:Transcriptional Activation; D019061:src-Family Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D024042:Collagen Type I; D011506:Proteins; D011975:Receptors, Mitogen; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases; D020778:Matrix Metalloproteinase 2