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

Genes Dev. 2012 Jul 1;26(13):1421-6. doi: 10.1101/gad.190876.112.

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.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cafe-au-Lait Spots / genetics
  • Cafe-au-Lait Spots / metabolism*
  • Cells, Cultured
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Neurofibromatosis 1 / genetics
  • Neurofibromatosis 1 / metabolism*
  • Neurofibromin 1 / genetics
  • Neurofibromin 1 / metabolism*
  • Protein Binding
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neurofibromin 1
  • Repressor Proteins
  • SPRED1 protein, human
  • Spred1 protein, mouse

Supplementary concepts

  • Legius syndrome