The vast unknown
Ask Martin Hemler, PhD, about tetraspanins, the focus of his research, and he replies, with a punch-line smile, "They're the largest family of human proteins that hardly anyone knows or cares about."
There is some truth in his statement. Coiling through the surface of a wide variety of human and other cell types, tetraspanins play a role in everything from mammalian fertilization to nerve development in fly embryos to fungal invasion in rice leaves. There are 32 known varieties, the vast majority of which have never been explored in detail.
The reasons for this neglect aren't hard to understand. Like a meadow covered with wildflowers, the surface of human cells holds dozens of different types of protein structures, each with a specific function. When scientists study cell signaling — in which cells snatch and release tiny substances from their surface — they tend to focus on the outer- and innermost parts of the protein structures (the crowns and roots, so to speak). Tetraspanins, which don't poke far through the cell surface or play a blatant role in binding, have been largely overlooked.
Cell-surface proteins called tetraspanins interact with other,
larger proteins called integrins to anchor cells in place.
Illustration by John DiGianni
Not by Hemler, however, who admits he was attracted to the field precisely because it appeals to his instinct for the less-trodden path.
Tetraspanins—so named because they're woven into the cell surface in such a way that they cross the outer membrane four ("tetra") times—have drawn Hemler's interest since the early ë80s. Although the protein makeup of a tetraspanin was first deciphered more than 15 years ago, scientists have only recently come to appreciate how versatile these structures are. Today, they're known to be involved in cell growth and proliferation, cell fusion (between egg and sperm cells, for instance), infectious disease, and cell mobility. It is this last area, which encompasses cells' capacity to move and infiltrate other tissue, that tetraspanins' role in metastasis is clearest.
Scientists have found, for example, that when a tetraspanin called CD9 is lacking in certain lung, pancreatic, and colorectal cancer cells, patients' prognosis tends to be poor—a sign that CD9 normally keeps cells from metastasizing. On the other hand, lung cancer cells with an oversupply of the tetraspanin CD151 are more likely to spread.
"Clearly, some tetraspanins enhance cell motility [movement], while others suppress it," Hemler remarks. His goal is to discover the mechanism that makes this so and learn whether it can be tweaked.
The key is not just tetraspanins themselves, but their interactions with other dwellers on the cell surface, particularly a family of proteins called integrins. Rising from the outer membrane, integrins grab onto the "extracellular matrix," the knobby tissue that holds cells in place. At the base of the integrins, hugging them like shrubs, are tetraspanins.
"The tetraspanins' job is to recruit other proteins involved in adhesion to the matrix," Hemler says. Using high-powered technology called mass spectrometry, he and his colleagues have identified exactly what some of these proteins are, for both CD151 and CD9.
The next step will be to determine which of these proteins play a role in suppressing metastasis. "Tetraspanins don't act in isolation," Hemler observes. "Understanding the proteins they work in concert with may eventually be important in designing therapies against metastasis"—a result that will not only benefit patients, but vindicate Hemler's exploration of what once was a backwater of cell biology.
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