Regulation of the Neurofibromatosis Type 2 Tumor Suppressor Protein, Merlin, by Adhesion and Growth Arrest Stimuli*
- From the Center for Cancer Research and Department of Biology, and§Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Abstract
The neurofibromatosis type 2 tumor suppressor gene is inactivated in the development of familial and sporadic schwannomas and meningiomas. The encoded protein, Merlin, is closely related to the Ezrin, Radixin, and Moesin family of membrane/cytoskeletal linker proteins. Examination of Merlin in several cell lines revealed that the protein migrates as two distinct species near 70 kDa. Phosphatase treatment and orthophosphate labeling demonstrated that the species with decreased mobility is phosphorylated. Given Merlin’s localization to cortical actin structures, we examined the effect of cell-cell contact or other forms of growth arrest on Merlin expression and post-translational modification. Under conditions of confluency or serum deprivation, the levels of phosphorylated and unphosphorylated Merlin species increased significantly. Cells arrested in G1 by other methods or other phases of the cell cycle did not show changes in Merlin levels. Furthermore, loss of adhesion resulted in a nearly complete dephosphorylation of Merlin, which was reversed upon re-plating of cells, suggesting Merlin phosphorylation may be responsive to cell spreading or changes in cell shape. Thus, the tumor suppressor function of Merlin may involve the regulation of cellular responses to cues such as cell-cell contact, growth factor microenvironment, or changes in cell shape.
Footnotes
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↵* This work was supported in part by a grant from the Department of Defense.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ Supported by fellowships from the National Neurofibromatosis Foundation and the Medallion Foundation and is currently a recipient of a Burroughs-Wellcome Career award. Present address: Massachusetts General Hospital Cancer Center and Harvard Medical School, Dept. of Pathology, Charlestown, MA 02129.
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↵¶ Associate Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed. Tel.: 617-253-0262; Fax: 617-253-9863; E-mail: tjacks{at}mit.edu.
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↵1 The abbreviations used are: NF2, neurofibromatosis type II; DMEM, Dulbecco’s minimum essential medium; PBS, phosphate-buffered saline; ES, embryonic stem; CCD, cytochalasin D; CIP, calf intestinal phosphatase; NRK, normal rat kidney.
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↵2 A. I. McClatchey, unpublished observations
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↵3 R. J. Shaw, A. I. McClatchey, and T. Jacks, submitted for publication.
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↵4 A. I. McClatchey, I. Saotome, K. Mercer, D. Crowley, J. Gusella, R. Bronson, and T. Jacks, submitted for publication.
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- Received August 29, 1997.
- Revision received December 12, 1997.
- The American Society for Biochemistry and Molecular Biology, Inc.
