Scientists show nuclear protein Ezh2 helps establish previously unknown signaling pathway in cells

Since 2001, scientists have wrestled with the discovery that there are fewer genes in humans than biological processes linked to those genes over the course of a human lifespan. One way to understand genetically coded events is by studying epigenetics, the regulation and heritability of genes at a cellular level due to molecular changes to the many proteins (called histones) that package DNA in a cell's nucleus. Though not a new concept, research in epigenetics has immensely contributed over the past four years to more nuanced explanations of biology.

Rockefeller University scientists now have moved a step beyond epigenetics in describing how genetically driven activities are carried out. Working with an important molecule, called Ezh2, known to alter histones in the cell nucleus, Sasha Tarakhovsky, Ph.D., and his colleagues have discovered a new type of signaling system in the cytosol, the fluid or jelly-like substance outside of a cell's nucleus. The research, published in the May 6 issue of Cell, suggests that proteins that control histone function also may function in the cytosol, where they coordinate signals generated at the cell membrane. Because Ezh2 is found in some cancer cells in abnormally high levels, the finding may provide new clues to how cancer cells spread throughout the body.

The researchers, led by first author I-hsin Su, Ph.D., a research associate in Tarakhovsky's laboratory, began with a scientific puzzle: Vav1, an important protein found in the cytosol, teams up with Ezh2, which normally works in the nucleus. But no one understood how.

To their surprise, Su, Tarakhovsky and their colleagues discovered that Ezh2 is able to do its work in two different locations, not just in the nucleus. Ezh2 carries out a biochemical process called lysine methylation, which modifies the function of the DNA-bound histones. The nuclear modification can be compared with a set of important instructions that a particular cell type needs to follow during the lifespan of a single organism. Making those instructions relatively permanent aids the cell type but the gene and what it is capable of telling cells is not limited to a single cell type or activity.

Su found that Ezh2 is required in the cytosol for polymerization of a cellular protein called actin. Actin polymerization defines the shape and movement of an individual cell as well as its ability to interact with other cells in the organism. Su and her colleagues found that in the absence of Ezh2, immune system cells called lymphocytes are unable to function normally. They fail to move and interact with other immune system cells that give instructions about the presence of pathogens.

Understanding more about the molecular basis of actin polymerization may be a boon to cancer research. Both breast and prostate cancer express Ezh2 at abnormally high levels. While these findings were initially thought to reveal genetic or histone-dependent changes leading to cancer, they may, in fact, reflect the ability of the tumor cells to spread throughout the body via efficient actin-dependent invasion mechanisms.

The discovery that Ezh2 works in the cellular cytosol is exciting for scientists unraveling the complicated molecular interactions of epigenetics and signaling. "It means that lysine methylation, what Ezh2 biochemically accomplishes in the nucleus, may have more general implications than previously known," says Tarakhovsky, senior author and head of the Laboratory of Lymphocyte Signaling at Rockefeller University. The discovery suggests the existence of a new kind of signaling pathway with broad implications in health and disease, he says.

Evidence of Ezh2 and its effects in a new location in the cell suggest entirely new ways of understanding signaling. Like delivery of mail in everyday life, some routes get the messages delivered more quickly and reliably while others are useful only under special circumstances. The routes themselves, and their conditions, matter.

"Ezh2 in the cytosol reveals that modification of the proteins may be more reversible or less reversible," says Tarakhovsky. Phosphorylation and ubiquitination, for example, are highly reversible. Lysine methylation, as far as scientists know, is relatively stable. Based on what scientists already know about lysine methylation of the histones in the cell nucleus, Ezh2 functioning in similar fashion in the cytosol may lead to assembly of the signaling complexes that will be maintained as stable or "memorized," thus making subsequent signaling events more efficient. While it is tempting to understand signaling as simple patterns of sending and receiving biochemical messages, the reality is more complex.

Tarakhovsky, Su and their colleagues have more work to do in understanding all the molecules involved with Ezh2 and Vav1 in the cytosol. But their discovery is generating interest from other researchers in chromatin biology and cell signaling to learn more about lysine methylation in the cytosol.

Other Rockefeller University authors on this publication are Marc-Werner Dobenecker, Ephraim Dickinson, Matthew Oser, and Ashwin Basavaraj.

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