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A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1.
Genes Dev. 2012 Jul 01; 26(13):1421-6.GD

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.

Authors+Show Affiliations

Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94158, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22751498

Citation

Stowe, Irma B., et al. "A Shared Molecular Mechanism Underlies the Human Rasopathies Legius Syndrome and Neurofibromatosis-1." Genes & Development, vol. 26, no. 13, 2012, pp. 1421-6.
Stowe IB, Mercado EL, Stowe TR, et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes Dev. 2012;26(13):1421-6.
Stowe, I. B., Mercado, E. L., Stowe, T. R., Bell, E. L., Oses-Prieto, J. A., Hernández, H., Burlingame, A. L., & McCormick, F. (2012). A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes & Development, 26(13), 1421-6. https://doi.org/10.1101/gad.190876.112
Stowe IB, et al. A Shared Molecular Mechanism Underlies the Human Rasopathies Legius Syndrome and Neurofibromatosis-1. Genes Dev. 2012 Jul 1;26(13):1421-6. PubMed PMID: 22751498.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. AU - Stowe,Irma B, AU - Mercado,Ellen L, AU - Stowe,Timothy R, AU - Bell,Erika L, AU - Oses-Prieto,Juan A, AU - Hernández,Hilda, AU - Burlingame,Alma L, AU - McCormick,Frank, PY - 2012/7/4/entrez PY - 2012/7/4/pubmed PY - 2012/9/14/medline SP - 1421 EP - 6 JF - Genes & development JO - Genes Dev VL - 26 IS - 13 N2 - 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. SN - 1549-5477 UR - https://www.unboundmedicine.com/medline/citation/22751498/A_shared_molecular_mechanism_underlies_the_human_rasopathies_Legius_syndrome_and_Neurofibromatosis_1_ L2 - http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=22751498 DB - PRIME DP - Unbound Medicine ER -