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Functions of the v-Src protein tyrosine kinase
V Fincham1, M Frame, B Haefner
1Beatson Institute for Cancer Research Cancer Research Campaign Beatson Laboratories, Bearsden, Glasgow, Scotland, UK.
Abstract:
The peripheral non-receptor tyrosine kinase oncoprotein, v-Src, has pleiotropic effects. It is a mitogen for quiescent cells, substituting for both competence and progression factor-mediated signals but it also induces cellular morphological transformation. We are dissecting the activities of v-Src by studying mutant proteins, including those with temperature sensitive (ts) effects, in different cellular backgrounds. Activation of a ts v-Src kinase rapidly increases activity of both the transcription factor, AP-1, and MAP kinase, an enzyme that enhances AP-1 activity by both phosphorylation of c-Jun and increased c-fos transcription; the relative contribution of these two events depends on the cells in which v-Src is expressed. Transient early AP-1 activation requires proper location of v-Src at the cell periphery and it is essential for mitogenesis. It is not, however, sufficient for entry into S-phase, there being a second need for v-Src later in G1. Transformation by v-Src does not require AP-1 activation but seems linked to events at the cell periphery, notably phosphorylation of proteins that bind to the v-Src SH3 domain such as the p85 subunit of PI-3 kinase.
Insights
The oncogenic protein v-Src drives cell growth and transformation. Its peripheral localization is crucial for early AP-1 activation, essential for cell division, but not for transformation.
Area of Science:
- Cell Biology
- Molecular Oncology
- Signal Transduction
Background:
- The v-Src oncoprotein, a peripheral non-receptor tyrosine kinase, exhibits diverse cellular effects.
- v-Src acts as a mitogen, replacing growth factor signals, and induces morphological transformation.
- Understanding v-Src's distinct activities is crucial for cancer research.
Purpose of the Study:
- To dissect the pleiotropic activities of v-Src using mutant proteins.
- To investigate the role of v-Src localization and downstream signaling in cell cycle progression and transformation.
- To differentiate the mechanisms underlying v-Src-mediated mitogenesis and transformation.
Main Methods:
- Utilized temperature-sensitive (ts) v-Src mutants in various cellular backgrounds.
- Assessed the activation of transcription factor AP-1 and MAP kinase upon v-Src activation.
- Examined the requirement of v-Src peripheral localization and SH3 domain interactions for its functions.
Main Results:
- Rapid activation of AP-1 and MAP kinase occurs upon v-Src kinase activation.
- Transient AP-1 activation requires v-Src's peripheral localization and is essential for mitogenesis but not S-phase entry.
- Cellular transformation by v-Src is independent of AP-1 activation and linked to peripheral events, including PI-3 kinase pathway modulation.
Conclusions:
- v-Src employs distinct pathways for mitogenesis and transformation.
- Peripheral v-Src localization and AP-1 activation are critical for cell proliferation.
- Transformation induced by v-Src involves peripheral signaling events independent of AP-1 activation.