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Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen
Kazuo Ikeda1, Li-Hsien Wang, Richard Torres
1Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA.
Abstract:
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.
Insights
Discoidin domain receptor 2 (DDR2) signaling requires Src kinase activity for maximal phosphorylation and interaction with the adaptor protein Shc. This cooperation is crucial for DDR2-mediated matrix metalloproteinase-2 promoter activation.
Area of Science:
- Cellular signaling pathways
- Receptor tyrosine kinases
- Biochemistry
Background:
- Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase activated by fibrillar collagen.
- Its precise signal transduction mechanisms, particularly in relation to other kinases, are not fully elucidated.
Purpose of the Study:
- To investigate the signal transduction pathways regulated by DDR2.
- To identify key signaling intermediates involved in DDR2 activation and downstream effects.
Main Methods:
- Analysis of DDR2 tyrosine-phosphorylation levels.
- Assessment of DDR2 association with signaling proteins like Shc.
- Investigation of DDR2's role in matrix metalloproteinase-2 (MMP-2) promoter activity.
Main Results:
- DDR2 requires Src kinase activity for maximal tyrosine-phosphorylation.
- Src activity promotes the association of DDR2 with Shc via a novel interaction site.
- Src is essential for DDR2-mediated transactivation of the MMP-2 promoter.
Conclusions:
- Src kinase and Shc are critical signaling intermediates in DDR2 pathways.
- A cooperative model between Src and DDR2 regulates receptor phosphorylation and target activation.