Photo of Dr. Julien Sage.
May 22nd, 2014, Stanford Medicine Scope, by Krista Conger
Eavesdropping on conversations among proteins is one way for researchers to understand how cells make decisions to divide or die, to move or to stay put, to respond to or ignore the insistent signals from a neighboring cell. Often these messages are passed from protein to protein within the cell, like a molecular game of “telephone”, via the transfer of small chemical tags like phosphate groups. These tags regulate the activity of a protein and affect how it interacts with other, downstream partners.
Understanding these messaging pathways is even more important when they become corrupted. As a result, cells can divide uncontrollably or (in the case of immune cells) launch attacks on other, harmless bystander cells or tissues.
Many of the message trails, called pathways, are governed by one or two loudmouths. One, known as the Ras family of proteins, is critically important to cell growth. In fact, the three Ras genes are among the most frequently mutated class of genes in human cancers. But it’s been very difficult to find effective ways to gag the Ras genes and their troublesome proteins. Recently, the National Cancer Institute pegged the molecule for special attention with its Ras Program, meant to encourage researchers to develop new, innovative ways to curb either the activity of the mutant Ras proteins or to inhibit the Ras pathway in other ways.
Now, cancer biologist Julien Sage, PhD, and biologist Or Gozani, MD, PhD, have identified a new signaling protein that works on another protein participant in the Ras pathway. Unlike the phosphate groups often passed from protein to protein in our example, this pathway relies instead on the transfer of what’s known as a methyl group from one protein to another. Their work was published (subscription required) yesterday in Nature. Sage explained the research to me in an e-mail:
A large number of human cancers are driven by activation of the Ras pathway, including pancreatic cancer and a subset of lung cancers. This observation has led to the development of small molecule inhibitors that target kinases (enzymes that add phosphate groups to other proteins) in the Ras signaling network. However, these drugs can be toxic and resistance can occur fairly rapidly. In this study, we found that the SMYD3 methyltransferase (an enzyme that adds methyl groups to other proteins) directly regulates the Ras pathway by adding a methyl group to a Ras pathway member (MAP3K2). In the absence of SMYD3, the Ras pathway is less active.
The researchers found that blocking SMYD3 expression in laboratory mice slowed the development of pancreatic and lung cancers when Ras genes were mutated. They also found that it had an important impact when the animals with cancers were treated with experimental Ras inhibitors. As Gozani explained:
Importantly, mice mutant for SMYD3 are completely viable but the dose of Ras pathway inhibitors required to inhibit pancreatic cancer growth is lower in SMYD3 mutant mice than in control mice. These experiments identify SMYD3 as a novel regulator of Ras signaling, one of the central oncogenic pathways in humans, and suggest that inhibitors targeting the methytransferase activity of SMYD3 may be combined with Ras pathway inhibitors to achieve lower toxicity and higher efficacy.
In other words, it might be possible to achieve greater therapeutic effect for some of these deadly cancers by hitting the Ras pathway twice. According to both Sage and Gozani:
This work establishes SMYD3 as a bona fide therapeutic target for pharmacologic intervention to treat some of the most deadly human cancers and argues that enzymes with similar functions might regulate crucial cellular pathways.
