Signal transduction pathways that regulate skeletal muscle gene expression.

The regulation of cellular functions by extracellular signaling molecules such as hormones, polypeptide growth factors, and neurotransmitters requires the generation of transient signals at the cell membrane, which are transmitted to the nucleus, where they result in short and long term changes in gene expression. One of the most common mechanisms for linking external signals to transcriptional responses is through protein kinase cascades that begin at cell surface receptors and culminate at transcription factors that coordinately regulate multiple target genes. Although changes in protein phosphorylation at the cell surface in response to receptor activation and the resulting alterations in expression of specific genes are well documented, the intermediate steps in signal transduction between the membrane and the nucleus are only beginning to be defined. Skeletal muscle cells are among the cell types whose properties are profoundly influenced by growth factors, hormones, and neurotransmitters. The recent identification of a small family of muscle-specific transcription factors that coordinately regulate gene expression in skeletal muscle and serve as targets for a variety of protein kinase cascades has revealed a potential end point for the cellular circuits that transduce signals from the cell membrane to the nucleus in muscle cells. This review will focus on evidence implicating protein kinases in the control of skeletal muscle cell growth, differentiation, and maturation. The possibility that muscle-specific transcription factors may serve as targets for protein kinase cascades will also be addressed, and several potential models to explain the regulation of muscle cell functions by protein kinases will be considered. For more comprehensive reviews on the regulation of muscle differentiation, the reader is referred to several recent reviews (l-5).