title: A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1.
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: Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94158, USA.
authors: Irma B
authors: IB
authors: Stowe
authors: Ellen L
authors: EL
authors: Mercado
authors: Timothy R
authors: TR
authors: Stowe
authors: Erika L
authors: EL
authors: Bell
authors: Juan A
authors: JA
authors: Oses-Prieto
authors: Hilda
authors: H
authors: Hernández
authors: Alma L
authors: AL
authors: Burlingame
authors: Frank
authors: F
authors: McCormick
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019080:Cafe-au-Lait Spots / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D025542:Neurofibromin 1; D012097:Repressor Proteins; C504812:SPRED1 protein, human; C433763:Spred1 protein, mouse