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Protein tyrosine phosphorylation in smooth muscle: a potential coupling mechanism between receptor activation and
J Di Salvo1, S R Nelson, N Kaplan
1Department of Physiology, University of Minnesota, Minneapolis 55455, USA.
Abstract:
This review addresses a rapidly growing body of evidence suggesting that enhanced protein tyrosine phosphorylation may be a previously unrecognized mechanism for coupling receptor activation of vascular smooth muscle cells to increases In the intracellular concentration of Ca2+ and contraction. The hypothesis proposes that activation of diverse types of receptors that are not tyrosine kinase promotes stimulation of a cytosolic tyrosine kinase. In turn, the activated kinase induces tyrosine phosphorylation of substrates that are linked to regulatory mechanisms for release of intracellular Ca2+ stored in the sarcoplasmic reticulum and to regulatory mechanisms for influx of extracellular Ca2+. Within this framework, we examine some relevant functional aspects of receptor and nonreceptor tyrosine kinases in different types of cells, the emerging relationships between tyrosine kinase activity and regulation of intracellular Ca2+. We review studies of nonreceptor tyrosine kinase activity in vascular smooth muscle cells suggesting that a physiologically relevant kinase may be the enzyme called pp60. Data that appear to link tyrosine phosphorylation to contraction of smooth muscle are examined, particularly with respect to results obtained with tyrosine kinase inhibitors and measures of changes in tyrosine phosphorylation. Next, we review studies with cultured vascular smooth muscle cells that point to potential coupling between receptor activation, enhanced tyrosine phosphorylation of substrates such as the GTPase activating protein for ras, and the gamma-1 isoform of phospholipase C, and mechanisms controlling Ca2+ influx and release. Emphasis is placed on examining the strengths and weaknesses of different experimental approaches. Lastly, a summary of the data is provided which calls attention to some major issues requiring resolution to permit acceptance or rejection of the underlying hypothesis, and we briefly address some of its possible pathophysiological implications.
Insights
Enhanced protein tyrosine phosphorylation may link receptor activation to vascular smooth muscle cell contraction by regulating intracellular calcium (Ca2+). This mechanism involves tyrosine kinases stimulating Ca2+ release and influx, impacting smooth muscle function.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cardiovascular Physiology
Background:
- Vascular smooth muscle cell (VSMC) contraction is crucial for regulating blood pressure.
- Receptor activation in VSMCs traditionally involves known signaling pathways.
- Emerging evidence suggests a role for protein tyrosine phosphorylation in VSMC responses.
Purpose of the Study:
- To review the evidence for protein tyrosine phosphorylation as a mechanism coupling receptor activation to Ca2+ handling and contraction in VSMCs.
- To examine the role of tyrosine kinases, including nonreceptor tyrosine kinases like pp60, in VSMC function.
- To explore the link between tyrosine phosphorylation, phospholipase C, and Ca2+ influx/release in cultured VSMCs.
Main Methods:
- Review of existing literature on tyrosine kinase activity, protein tyrosine phosphorylation, and Ca2+ signaling in VSMCs.
- Analysis of studies using tyrosine kinase inhibitors and measurements of tyrosine phosphorylation.
- Examination of experimental approaches investigating receptor-mediated signaling pathways in VSMCs.
Main Results:
- Receptor activation, independent of intrinsic tyrosine kinase activity, can stimulate cytosolic tyrosine kinases.
- Activated tyrosine kinases phosphorylate substrates, influencing intracellular Ca2+ release and extracellular Ca2+ influx.
- Studies suggest a link between tyrosine phosphorylation, GTPase activating protein for ras, and phospholipase C gamma-1 in VSMCs.
Conclusions:
- Protein tyrosine phosphorylation represents a potential, previously unrecognized mechanism for regulating VSMC Ca2+ and contraction.
- Further research is needed to confirm the role of specific tyrosine kinases and their substrates in this pathway.
- Understanding this mechanism may reveal novel pathophysiological implications for cardiovascular diseases.