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Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology

Nature Genetics volume 31, pages 354–362 (2002)Cite this article

Abstract

Neurofibromatosis type 2 is an autosomal dominant disorder characterized by tumors, predominantly schwannomas, in the nervous system. It is caused by mutations in the gene NF2, encoding the growth regulator schwannomin (also known as merlin). Mutations occur throughout the 17-exon gene, with most resulting in protein truncation and undetectable amounts of schwannomin protein. Pathogenic mutations that result in production of defective schwannomin include in-frame deletions of exon 2 and three independent missense mutations within this same exon. Mice with conditional deletion of exon 2 in Schwann cells develop schwannomas, which confirms the crucial nature of exon 2 for growth control. Here we report that the molecular adaptor paxillin binds directly to schwannomin at residues 50–70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with β1 integrin and erbB2. It defines a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2.

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Figure 1: Schwannomin coimunoprecipitates and colocalizes with β1 integrin.
Figure 2: Schwannomin and paxillin colocalize at the cell periphery in subconfluent cells.
Figure 3: Schwannomin and paxillin associate in Schwann cells.
Figure 4: Two PBDs are located at aa 50–70 and 425–450 in schwannomin.
Figure 5: Schwannomin variants ΔPBD1, Trp60Cys and Phe62Ser fail to bind paxillin.
Figure 6: PBD1 is required for membrane localization and polarization.
Figure 7: Schwannomin and paxillin associate with β1 integrin and erbB2 in a density-dependent manner.
Figure 8: Model of schwannomin interactions in proliferating and quiescent Schwann cells.

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Acknowledgements

We thank C. Turner for paxillin cDNA; S. Pulst and L. Sherman for discussions; and D. Bailey and E. Rodriguez for technical assistance. This work was supported by a US Public Health Service grant (to C.F.-V.), a National Neurofibromatosis Foundation Young Investigator Award (to J.R.) and the State of Florida.

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  1. Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, 32826, Florida, USA

    Cristina Fernandez-Valle, Yong Tang, Jerome Ricard, Alma Rodenas-Ruano, Anna Taylor, Elizabeth Hackler, John Biggerstaff & Jared Iacovelli

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Fernandez-Valle, C., Tang, Y., Ricard, J. et al. Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nat Genet 31, 354–362 (2002). https://doi.org/10.1038/ng930

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