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Development of Vascular Smooth Muscle Cells Depends on Signaling Synergy

Development of Vascular Smooth Muscle Cells Depends on Signaling Synergy


A multicellular organism can have more than 200 different types of cells and as many as 100 trillion altogether. During the process of development, an organism enlists the service of hundreds of signaling molecules and thousands of receptors to direct cell growth, differentiation, and morphological destiny. Any given cell has no use for most of these signals and gets by with just a limited repertoire of receptors on its surface. Once a signal reaches a receptor, it triggers a series of biochemical reactions as different molecules transform the external signal into a biological response, in a process called signal transduction. One cell type controls all of its cellular functions—both universal and specialized—with just a few dozen receptors; each receptor elicits a wide range of responses by triggering a small number of interacting pathways. Exactly how a receptor produces the right response at the right time is a fundamental question in biology.

Of particular interest is a class of receptors—called receptor tyrosine kinases (RTKs)—that regulate cell proliferation, differentiation, and survival and play an important role in embryonic development and disease. Growth factor receptors are an important subset of RTKs. The platelet-derived growth factor receptor (PDGFR) family activates downstream signaling enzymes that stimulate the growth and motility of connective tissue cells, such as vascular smooth muscle cells (VSMCs), oligodendrocytes (cells of the tissue encasing nerve fibers), and chondrocytes (cartilage cells). The PDGF beta receptor is essential for directing the differentiation of VSMCs. While studies of signal transduction of this growth factor have established a model of how receptor tyrosine kinases function, the role of individual downstream signaling components in a living organism is still unclear.

Using mouse molecular genetics, Michelle Tallquist and colleagues set out to determine the function of individual components in the PDGFR beta pathway. They discovered a quantitative correlation between the overall amount of signal produced by the receptor and the end product of the signal, formation of VSMCs. Receptor responses, they report, are controlled in two ways: signaling was influenced both by the amount of receptors expressed and by the number of specific pathways engaged downstream of the receptor.

Surface receptors have “tails” that project into a cell's interior. When a surface receptor is activated, a number of potential binding sites—modified amino acid residues—are exposed on its intracellular tail. Ten of these sites can bind to proteins with a specific amino acid sequence, called an SH2 domain; proteins with these domains can then initiate a signal transduction pathway. By introducing mutations in the SH2 domain-binding sites in mice, the researchers could evaluate how the loss of a particular binding site—and therefore pathway—affected the function of the receptor. They had previously investigated the functions of two other downstream signaling proteins in similar experiments.

Surprisingly, Tallquist et al. found that losing some of the individual components did not produce a significant negative physiological effect. Only when multiple downstream signaling pathways were disrupted did the researchers see a significant effect on the population of the cells. Reductions in the numbers of both activated receptors and activated signal transduction pathways produced reductions in the population of VSMCs. These results have not been seen in tissue culture before, suggesting that signal transduction is more complex in vivo and that future studies would benefit from incorporating a global approach, rather than targeting a single signaling component. The next step will be to investigate exactly how the individual pathways contribute to this result. It is also unclear whether these results apply only to these growth factor receptors or explain how RTKs operate in general.

Such questions have significant clinical relevance. Overexpression of the PDGFR beta pathway has been linked to a variety of serious diseases, including atherosclerosis and cancer. Understanding how cells control the action of this growth factor is an important step in developing targeted therapies. Since many of these conditions result from a growth factor stuck in the “on” position, inhibiting overactive receptors promises to be an effective clinical intervention.