A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1
- Irma B. Stowe1,
- Ellen L. Mercado1,
- Timothy R. Stowe2,
- Erika L. Bell1,
- Juan A. Oses-Prieto3,
- Hilda Hernández3,
- Alma L. Burlingame3 and
- Frank McCormick1,4
- 1Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94158, USA;
- 2Department of Neurological Surgery, University of California at San Francisco, San Francisco, California 94143, USA;
- 3Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143, USA
Abstract
The Ras/mitogen-activated protein kinase (MAPK) pathway plays a critical role in transducing mitogenic signals from receptor tyrosine kinases. Loss-of-function mutations in one feedback regulator of Ras/MAPK signaling, SPRED1 (Sprouty-related protein with an EVH1 domain), cause Legius syndrome, an autosomal dominant human disorder that resembles Neurofibromatosis-1 (NF1). Spred1 functions as a negative regulator of the Ras/MAPK pathway; however, the underlying molecular mechanism is poorly understood. Here we show that neurofibromin, the NF1 gene product, is a Spred1-interacting protein that is necessary for Spred1's inhibitory function. We show that Spred1 binding induces the plasma membrane localization of NF1, which subsequently down-regulates Ras-GTP levels. This novel mechanism for the regulation of neurofibromin provides a molecular bridge for understanding the overlapping pathophysiology of NF1 and Legius syndrome.
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Footnotes
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↵4 Corresponding author
E-mail mccormick{at}cc.ucsf.edu
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.190876.112.
- Received February 28, 2012.
- Accepted May 25, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press
