Related Experiment Video
Updated: Mar 23, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Novel autophosphorylation sites of Src family kinases regulate kinase activity and SH2 domain-binding capacity
Marion E Weir1, Jacqueline E Mann2, Thomas Corwin3
1Department of Biology, University of Vermont, Burlington, VT, USA.
Abstract:
Src family tyrosine kinases (SFKs) are critical players in normal and aberrant biological processes. While phosphorylation importantly regulates SFKs at two known tyrosines, large-scale phosphoproteomics have revealed four additional tyrosines commonly phosphorylated in SFKs. We found these novel tyrosines to be autophosphorylation sites. Mimicking phosphorylation at the C-terminal site to the activation loop decreased Fyn activity. Phosphomimetics and direct phosphorylation at the three SH2 domain sites increased Fyn activity while reducing phosphotyrosine-dependent interactions. While 68% of human SH2 domains exhibit conservation of at least one of these tyrosines, few have been found phosphorylated except when found in cis to a kinase domain.
Insights
New phosphorylation sites on Src family tyrosine kinases (SFKs) were discovered. These sites regulate SFK activity and protein interactions, offering new insights into kinase regulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Src family tyrosine kinases (SFKs) are crucial regulators of cellular processes.
- Known phosphorylation sites on SFKs are key to their activity.
- Previous studies identified two regulatory tyrosine phosphorylation sites.
Discussion:
- Large-scale phosphoproteomics identified four novel tyrosine phosphorylation sites on SFKs.
- These sites were confirmed as autophosphorylation sites.
- Phosphorylation at the C-terminal site decreased Fyn activity, while SH2 domain site phosphorylation increased Fyn activity.
Key Insights:
- Novel autophosphorylation sites on SFKs significantly impact kinase activity.
- Phosphorylation at SH2 domain sites modulates phosphotyrosine-dependent interactions.
- Conserved tyrosine sites in SH2 domains suggest broader regulatory roles.
Outlook:
- Further investigation into these novel sites could reveal new therapeutic targets.
- Understanding SFK phosphorylation dynamics is vital for comprehending signaling pathways.
- Exploring the role of these sites in disease states is warranted.
Related Concept Videos
01:20The JAK-STAT Signaling Pathway
01:26Receptor Tyrosine Kinases
01:22Amplifying Signals via Enzymatic Cascade
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
02:54Protein Kinases and Phosphatases
01:02Phosphorylation
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...