An international team of scientists lead by Dr. Peter Herrlich at the University of Karlsruhe in Germany has discovered how the tumor suppressor, merlin, functions. Mutations in merlin cause Neurofibromatosis type 2 (NF2), a common inherited disorder that features the predisposition to develop multiple benign tumors of the central nervous system. Published in Genes & Development, this work delineates the pathway by which cells that are mutant in merlin become tumorigenic.
Cell density is one of several growth-limiting parameters. Normal cells proliferate until they occupy the space allotted to them, and stop proliferating once they contact other cells or a dense extracellular environment. Overcoming this contact growth inhibition is an integral aspect of cancer induction. Dr. Herrlich and colleagues have found that merlin is a key component of the mechanism by which a cell responds to contact inhibition.
Although previous studies have identified merlin as a negative regulator of cell growth, this paper is the first documentation of merlin’s specific role in the contact inhibition of growth. Under high cell density conditions, the extracellular portion of the cell membrane-spanning protein, CD44, binds to a specific component of the matrix that surrounds adjacent proliferating cells. Dr. Herrlich and colleagues have shown that once this occurs, merlin becomes desphosphorylated, and forms a tight bond with the intracellular portion of CD44. This activated form of merlin effectively blocks further cell proliferation.
The data presented in this paper has significant implications for the understanding of how merlin deficiency contributes to tumorigenesis. NF2 patients display multiple tumors derived from glial cells. This work suggests that because these glial cells lacked the merlin/CD44 growth regulatory switch, they were able to overcome contact growth inhibition. Although contact inhibition is only one form of cell growth regulation, the insight that Dr. Herrlich and colleagues have provided into the mechanism of contact growth inhibition will undoubtedly improve our understanding of cancer development.
Materials provided by Cold Spring Harbor Laboratory. Note: Content may be edited for style and length.
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