Human Molecular Genetics, 2002, Vol. 11, No. 25 3167-3178
© 2002 Oxford University Press
Functional analysis of the relationship between the neurofibromatosis 2 tumor suppressor and its binding partner, hepatocyte growth factor-regulated tyrosine kinase substrate
1Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA, 2Neurogenetics Laboratory, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA, 3INSERM U434, Fondation Jean Dausset CEPH, 75010 Paris, France and 4Department of Biological Sciences, Tokyo Institute of Technology, Yokohama, Japan
Received July 30, 2002; Accepted October 2, 2002
Individuals with the neurofibromatosis 2 (NF2) inherited tumor predisposition syndrome are prone to the development of nervous system tumors, including schwannomas and meningiomas. The NF2 tumor suppressor protein, merlin or schwannomin, inhibits cell growth and motility as well as affects actin cytoskeleton-mediated processes. Merlin interacts with several proteins that might mediate merlin growth suppression, including hepatocyte growth factor-regulated tyrosine kinase substrate (HRS or HGS). Previously, we demonstrated that regulated overexpression of HRS in RT4 rat schwannoma cells had the same functional consequences as regulated overexpression of merlin. To determine the functional significance of this interaction, we generated a series of HRS truncation mutants and defined the regions of HRS required for merlin binding and HRS growth suppression. The HRS domain required for merlin binding was narrowed to a region (residues 470–497) containing the predicted coiled-coil domain whereas the major domain responsible for HRS growth suppression was distinct (residues 498–550). To determine whether merlin growth suppression required HRS, we demonstrated that merlin inhibited growth in HRS +/+, but not HRS -/- mouse embryonic fibroblast cells. In contrast, HRS could suppress cell growth in the absence of Nf2 expression. These results suggest that merlin growth suppression requires HRS expression and that the binding of merlin to HRS may facilitate its ability to function as a tumor suppressor.
* To whom correspondence should be addressed at: Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA. Tel: +1 3143627379; Fax: +1 3143622388; Email: gutmannd{at}neuro.wustl.edu
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