News Release

The magic behind merlin

Peer-Reviewed Publication

Cold Spring Harbor Laboratory

A new study reveals an essential role for the merlin protein in maintaining the junctions between cells – a significant advance in understanding the tumor suppressor function of this protein, and how mutations in the gene that encodes it can contribute to cancer.

The report is published by Dr. Andrea McClatchey and colleagues at the MGH Cancer Center (Charlestown, MA) and INSERM (Paris, France) in the May 1 issue of Genes & Development.

The merlin protein is encoded by the NF2 gene. Mutations in NF2 cause neurofibromatosis type 2, a hereditary cancer syndrome characterized by a predisposition to develop tumors of the central nervous system. Although NF2 was cloned a decade ago, this paper by Dr. McClatchey and colleagues provides unprecedented insight into the biological consequences of merlin loss and therefore its role in tumorigenesis.

Dr. McClatchey and colleagues have determined that merlin resides in adherens junctions – the mechanical attachments that connect adjacent cells. In addition to providing support and rigidity to tissues, adherens junctions are also necessary for contact-mediated growth inhibition, the property of cells to cease proliferating once they occupy the space allotted to them and come in contact with other cells and/or a dense extracellular environment.

"We found that merlin normally controls the way cells communicate with each other; merlin-deficient cells cannot 'sense' each other and continue to divide when there is no more room," states Dr. McClatchey.

Dr. McCatchey and colleagues used Nf2-deficient mouse cells to demonstrate that the absence of merlin results in the destabilization of adherens junctions and the subsequent loss of contact-mediated growth inhibition. The researchers were able to observe Nf2-deficient cells piling up on top of each other, seemingly immune to the contact-mediated growth arrest signal. However, the exogenous expression of merlin protein in Nf2-deficient cells is sufficient to restore both adherens junction formation and contact-mediated growth inhibition.

This newly identified function of merlin in the formation and maintenance of adherens junctions provides a molecular basis for its role in suppressing the development and progression of cancer. As Dr. McClatchey explains, "Loss of adherens junction integrity has been linked to both tumor development and tumor invasion, providing an explanation for the striking development of metastatic cancer in Nf2-mutant mice. The control of macromolecular assembly at the cell membrane represents a novel mechanism of tumor suppressor function and may represent a paradigm for the study of other cancer-associated proteins. In fact, this study, together with the study of cancer development in Nf2-mutant mice suggests that the role of NF2 inactivation in human cancer development and metastasis may be quite underappreciated."

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