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C-terminal Src kinase associates with ligand-stimulated insulin-like growth factor-I receptor
C Arbet-Engels1, S Tartare-Deckert, W Eckhart
1Molecular Biology and Virology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. arbet@axp1.salk.edu
Abstract:
Increased expression of the insulin-like growth factor-I receptor (IGF-IR) protein-tyrosine kinase occurs in several kinds of cancer and induces neoplastic transformation in fibroblast cell lines. The transformed phenotype can be reversed by interfering with the function of the IGF-IR. The IGF-IR is required for transformation by a number of viral and cellular oncoproteins, including SV40 large T antigen, Ras, Raf, and Src. The IGF-IR is a substrate for Src in vitro and is phosphorylated in v-Src-transformed cells. We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation. We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR. We determined the tyrosine residues in the IGF-IR and in the IR responsible for this interaction. We also observed that fibroblasts stimulated with IGF-I or insulin showed a rapid and transient decrease in c-Src tyrosine kinase activity. The results suggest that c-Src and CSK are involved in IGF-IR and IR signaling and that the interaction of CSK with the IGF-IR may play a role in the decrease in c-Src activity following IGF-I stimulation.
Insights
The insulin-like growth factor-I receptor (IGF-IR) interacts with C-terminal Src kinase (CSK), influencing cancer cell transformation. This interaction may regulate c-Src activity in response to IGF-I signaling.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Increased insulin-like growth factor-I receptor (IGF-IR) expression is linked to various cancers.
- IGF-IR signaling is crucial for neoplastic transformation and can be targeted to reverse it.
- IGF-IR is essential for transformation mediated by oncoproteins like Src.
Purpose of the Study:
- To investigate the interaction between IGF-IR, insulin receptor (IR), and C-terminal Src kinase (CSK).
- To elucidate the role of this interaction in regulating Src kinase activity during IGF-I and insulin signaling.
Main Methods:
- Studied the association of IGF-IR and IR with CSK after ligand stimulation.
- Utilized techniques to identify the binding sites (SH2 domain of CSK and tyrosine residues on receptors) for interaction.
- Assessed the impact of IGF-I and insulin stimulation on c-Src tyrosine kinase activity in fibroblasts.
Main Results:
- IGF-IR and IR associate with CSK upon ligand stimulation.
- CSK's SH2 domain binds to tyrosine-phosphorylated IGF-IR and IR.
- Identified specific tyrosine residues involved in the CSK-receptor interaction.
- Observed a transient decrease in c-Src activity following IGF-I or insulin stimulation.
Conclusions:
- c-Src and CSK are integral components of IGF-IR and IR signaling pathways.
- The interaction between CSK and IGF-IR may mediate the observed decrease in c-Src activity after IGF-I stimulation.
- Findings suggest a regulatory mechanism involving CSK in IGF-IR signaling relevant to cancer biology.