Tumors, both cancerous and noncancerous, can arise when cellular pathways that control cell proliferation and tissue growth go awry. Many ongoing research efforts are underway to identify the crucial genetic underpinning of such pathways.
This knowledge can help us locate useful biomarkers that reliably identify at risk individuals as well as aide in the discovery of potential drug treatments.
The efforts of Pan and his research group at Hopkins represent some of the latest success in this effort. 10 years ago, his group identified a gene in fruit flies that was important in regulating organ growth in proportion to the overall size of the fly. They discovered that without this gene, affected fruit flies developed unusually large and wrinkled organs, and aptly dubbed the gene Hippo. Since their discovery, Pan’s lab, as well as others, have been dedicated to understanding exactly how the Hippo gene achieves its function.
Recent work published by Pan have come to bear some of the fruits of this approach. Their work focuses on understanding the effect of a protein called Merlin, also known as NF2 in humans. Merlin is found in the cytoskeleton of cells — the structural layer underneath the cell membrane.
Previous work has shown that Merlin functions as a tumor suppressor. While others have demonstrated that mutating the gene in humans can cause neurofibromatosis type 2, a noncancerous tumor that applies pressure to neural tissue in the brain and spinal cord, resulting in impaired vision, hearing and other functions pertaining to the affected neural tissue. However researchers believe that the implications of Merlin and its associated pathways reach beyond neurofibromatosis type 2.
Previous work has shown that Merlin may be causing the effect as part of the Hippo pathway (previously identified by Pan). However, until now, no one has been able to provide a thorough mechanism for Merlin protein action. Pan and his research team have demonstrated that the Merlin serves as a pathway bridge; it’s function is to bring together two elements of the Hippo pathway: the Hpo Protein itself and another protein called Wts (Lats ½ in mammals). By providing an anchoring site for the Wts, Merlin allows it to get close enough to the Hippo protein to allow Hippo to activate it and continue the pathway.
This discovery challenges the preconceived idea that Merlin was just another element in a linear cascade towards Hippo activation. This was proven with a technique known as immunoprecipitation. It involves the design of antibodies that specifically bind to a desired protein target which in turn can be coupled with a fluorescent marker; the level of light measured from the fluorescent activity can be interpreted as an indicator of how active that protein is in the cell.
This is a very powerful technique used in a lot of pathway research. What Pan and his team found was that while cells that had the gene for Mer protein did not show higher levels of activated Hpo protein, they did show higher levels of Wts activity. These were results were similarly demonstrated in human cells as well. This provides direct evidence against the linear cascade model, and actually supports the mechanism proposed by Pan and his team.
This work represents a step forward in understanding how Merlin actually achieves its antitumor qualities. An understanding of this mechanism and others like it represent crucial information for the identification of treatment targets for cancers in the future.