Protein Complex Regulating How Epithelial Cells Bond Together May Lead to New Cancer Insights

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Rafael Garcia-Mata
Dr. Rafael Garcia-Mata, associate professor of biological sciences at The University of Toledo. [Daniel Miller, The University of Toledo]

Scientists at the University of Toledo led by Rafael Garcia-Mata, PhD, an associate professor of biological sciences, have identified a protein complex that regulates how epithelial cells bond together. There are more than 150 different types of epithelial cells that carry out essential functions in a wide variety of tissues. Those jobs include making our skin resilient, producing the mucus that lines and guards our airways, and helping with the absorption of nutrients in our digestive system.

The discovery, which builds on previous research on how cancer cells spread throughout the body, is intriguing because it explains the behavior of cells that are by far the most common starting place for cancer, according to Garcia-Mata.

“Eighty percent of cancers originate from epithelial cells and most cancers will have to disassemble the adhesion system to grow and spread,” Garcia-Mata said. “If we understand how these adhesive structures are built, we can also try to understand what happens when cancer cells disassemble them.”

His team published its study (“SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility”) in the Journal of Cell Biology.

“The canonical Scribble polarity complex is implicated in regulation of epithelial junctions and apical polarity. Here, we show that SGEF, a RhoG-specific GEF, forms a ternary complex with Scribble and Dlg1, two members of the Scribble complex. SGEF targets to apical junctions in a Scribble-dependent fashion and functions in the regulation of actomyosin-based contractility and barrier function at tight junctions as well as E-cadherin–mediated formation of adherens junctions. Surprisingly, SGEF does not control the establishment of polarity,” the investigators wrote.

“However, in 3D cysts, SGEF regulates the formation of a single open lumen. Interestingly, SGEF’s nucleotide exchange activity regulates the formation and maintenance of adherens junctions, and in cysts the number of lumens formed, whereas SGEF’s scaffolding activity is critical for regulation of actomyosin contractility and lumen opening. We propose that SGEF plays a key role in coordinating junctional assembly and actomyosin contractility by bringing together Scribble and Dlg1 and targeting RhoG activation to cell–cell junctions.”

Epithelial tissues line the outer surfaces of organs and blood vessels throughout the body, as well as the inner surfaces of cavities in many internal organs. Their ability to form nearly impermeable junctions enables them to establish boundaries that separate the inside of organs and other tissues from the outside environment.

The way epithelial cells link together is unique in biology and involves a large number of components that work in synchrony to control their assembly. However, the science behind how they manage to form such perfect bonds has up to now been elusive.

“The way these cells organize is very important. What we’ve identified is a new molecular mechanism that controls a lot of the properties that make the ‘right’ epithelial tissues,” noted Garcia-Mata. “Understanding how they normally function allows you to understand what happens when things go wrong.”

The implications of these findings go well beyond cancer, added Garcia-Mata, whose research also helps explain how cells coordinate to generate organ cavities, which may broaden our knowledge of early development and organ formation. It could add significant new pathways for explaining conditions such as asthma and inflammatory bowel disease.

“A lot of diseases are essentially leaky epithelia. Understanding how these structures are modulated may help us learn why we get some of these diseases,” he continued.

Garcia-Mata’s research into epithelial cells grew out of prior National Institutes of Health grant-funded work investigating how cancer cells spread away from the primary tumor.

“My lab studies basic, hardcore cell biology. This is where we make discoveries that lead to our ability to understand and target particular diseases, and the initial event in most cancers is the disassembly of these epithelial structures,” he pointed out.

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