Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling

Cell Signal. 2007 Jun;19(6):1279-89. doi: 10.1016/j.cellsig.2007.01.013. Epub 2007 Jan 20.


Human Sin1 (SAPK-interacting protein 1) is a member of a conserved family of orthologous proteins that have an essential role in signal transduction in yeast and Dictyostelium. This study demonstrates that most Sin1 orthologues contain both a Raf-like Ras-binding domain (RBD) and a pleckstrin homology (PH) domain. These domains are functional in the human Sin1 protein, with the PH domain involved in lipid and membrane binding by Sin1, and the RBD able to bind activated H-and K-Ras. Sin1 and Ras co-immunoprecipitated and co-localised, showing that these proteins associate with each other in vivo. Overexpression of Sin1 inhibited the activation of ERK, Akt and JNK signalling pathways by Ras. In contrast, siRNA knockdown of endogenous Sin1 protein expression in HEK293 cells enhanced the activation of ERK1/2 by Ras. These data suggest that Sin1 is a mammalian Ras-inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry*
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Cricetinae
  • Enzyme Activation
  • Humans
  • Lipids
  • Molecular Sequence Data
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Signal Transduction*
  • ras Proteins / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Lipids
  • MAPKAP1 protein, human
  • ras Proteins