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Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells
L E Marengère1, C Mirtsos, I Kozieradzki
1Amgen Institute, and Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Journal of Immunology (Baltimore, Md. : 1950)
|July 1, 1997
Summary
The molecular adapter c-Cbl links T cell receptor (TCR) activation to Ras signaling pathways. This study reveals that c-Cbl forms complexes with Vav, a key regulator in T cell development and activation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- The molecular adapter c-Cbl is tyrosine phosphorylated upon T cell receptor (TCR) stimulation, associating with SH2/SH3 domain-containing adapters.
- These adapters link TCR activation to Ras family GTP binding protein regulators.
- Vav, another SH2/SH3 domain-containing protein with guanine nucleotide exchange factor activity, plays a critical role in T cell development and activation.
Purpose of the Study:
- To investigate the molecular interaction between Vav and c-Cbl in T cells.
- To determine the role of c-Cbl as a molecular adapter in regulating Vav function.
Main Methods:
- Co-immunoprecipitation assays to detect molecular complexes.
- Analysis of T cells from wild-type and gene-targeted mice (CTLA-4 deficient).
- In vitro binding assays to identify specific interaction motifs.
Main Results:
- Vav and c-Cbl form inducible molecular complexes in TCR-activated and pervanadate-treated T cells.
- This interaction is observed in T cells from CTLA-4 deficient mice, where c-Cbl is hyperphosphorylated.
- The interaction is mediated by the Vav SH2 domain binding to tyrosine-phosphorylated c-Cbl, specifically at the Y699 MTP motif.
Conclusions:
- c-Cbl acts as a molecular adapter that regulates Vav function in thymocytes and peripheral T cells.
- The interaction between Vav and c-Cbl is crucial for T cell signaling pathways downstream of TCR activation.