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Ras activity is required for phenylephrine-induced activation of mitogen-activated protein kinase in cardiac muscle
1Dept. of Human Genetics, Eccles Institute of Human Genetics, University of Utah, Salt Lake City 84112.
Abstract:
The mitogen-activated protein (MAP) kinases are a family of kinases whose activity is implicated in a number of growth and differentiation responses. Recently, we and others have shown that these kinases are activated by agonists which induce cardiac muscle cell hypertrophy. Inhibition of MAP kinase activation prevents some of the phenotypes associated with phenylephrine-induced cardiac cell hypertrophy, indicating that this activation is of functional significance. In this communication, we show that active Ras can induce MAP kinase activation in cardiac muscle cells. In addition, phenylephrine-induced activation of the MAP kinases requires Ras activity since a dominant negative Ras mutant (Ala15Ras) and a Ras-blocking, Raf mutant (C4B Raf) prevent activation of the MAP kinase Erk2 by phenylephrine. These data indicate that phenylephrine signaling to the MAP kinases is mediated through Ras.
Insights
Mitogen-activated protein (MAP) kinases are crucial for cell growth and differentiation. This study reveals that Ras proteins mediate the activation of MAP kinases, a key signaling pathway in cardiac muscle cells during hypertrophy.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Cardiovascular research
Background:
- Mitogen-activated protein (MAP) kinases regulate critical cellular processes like growth and differentiation.
- MAP kinase activation is implicated in cardiac muscle cell hypertrophy.
- Previous research suggests MAP kinase activation is functionally significant in phenylephrine-induced cardiac hypertrophy.
Purpose of the Study:
- To investigate the role of Ras proteins in MAP kinase activation within cardiac muscle cells.
- To determine if Ras activity is required for phenylephrine-induced MAP kinase activation.
Main Methods:
- Utilized dominant-negative Ras mutants (Ala15Ras) to inhibit Ras activity.
- Employed a Ras-blocking Raf mutant (C4B Raf) to impede downstream signaling.
- Assessed the activation of the MAP kinase Erk2 in response to phenylephrine stimulation.
Main Results:
- Active Ras was demonstrated to induce MAP kinase activation in cardiac muscle cells.
- Phenylephrine-induced activation of MAP kinases was significantly inhibited by dominant-negative Ras and Ras-blocking Raf mutants.
- These findings pinpoint Ras as a critical mediator in the phenylephrine signaling pathway to MAP kinases.
Conclusions:
- Ras proteins play a pivotal role in mediating MAP kinase activation in cardiac muscle cells.
- Phenylephrine signaling to MAP kinases is dependent on Ras activity.
- Understanding this pathway is crucial for comprehending cardiac hypertrophy mechanisms.