A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1

作者：Stowe Irma B; Mercado Ellen L; Stowe Timothy R; Bell Erika L; Oses Prieto Juan A; Hernandez Hilda; Burlingame Alma L; McCormick Frank^*

来源：Genes & Development, 2012, 26(13): 1421-1426.

DOI：10.1101/gad.190876.112

• Legius syndrome
• NF1
• signal transduction
• Ras/MAPK
• Sprouty

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.

• 出版日期2012-7-1