Human Molecular Genetics, 2000, Vol. 9, No. 11 1567-1574
© 2000 Oxford University Press
The neurofibromatosis 2 tumor suppressor protein interacts with hepatocyte growth factor-regulated tyrosine kinase substrate
1Neurogenetics Laboratory, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, School of Medicine, University of California at Los Angeles, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA, 2Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St Louis, MO 63110, USA and 3Division of Neurology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, 8631 West 3rd Street, 1145E, Los Angeles, CA 90048, USA
The neurofibromatosis 2 tumor suppressor protein schwannomin/merlin is commonly mutated in schwannomas and meningiomas. Schwannomin, a member of the 4.1 family of proteins, which are known to link the cytoskeleton to the plasma membrane, has little known function other than its ability to suppress tumor growth. Using yeast two-hybrid interaction cloning, we identified the HGF-regulated tyrosine kinase substrate (HRS) as a schwannomin interactor. We verified the interaction by both immunoprecipitation of endogenous HRS with endogenous schwannomin in vivo as well as by using bacterially purified HRS and schwannomin in vitro. We narrowed the regions of interaction to include schwannomin residues 256–579 and HRS residues from 480 to the end of either of two HRS isoforms. Schwannomin molecules with a L46R, L360P, L535P or Q538P missense mutation demonstrated reduced affinity for HRS binding. As HRS is associated with early endosomes and may mediate receptor translocation to the lysosome, we demonstrated that schwannomin and HRS co-localize at endosomes using the early endosome antigen 1 in STS26T Schwann cells by indirect immunofluorescence. The identification of schwannomin as a HRS interactor implicates schwannomin in HRS-mediated cell signaling.
+ To whom correspondence should be addressed at: Division of Neurology, Cedars-Sinai Medical Center, Suite 1145E, 8631 West 3rd Street, Los Angeles, CA 90048, USA. Tel: +1 310 423 5166; Fax: +1 310 423 0149; Email: pulst@cshs.org
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