Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation

Biochem Biophys Res Commun. 2003 Mar 21;302(4):767-72. doi: 10.1016/s0006-291x(03)00259-6.


We have reported on Spred-1 and Spred-2, which inhibit MAP kinase activation by interacting with c-kit and ras/raf. Here, we report the cloning of a third member in this family, Spred-3. Spred-3 is expressed exclusively in the brain and its gene locates in chromosome 19q13.13 in human. Like Spred-1 and -2, Spred-3 contains an EVH1 domain in the N-terminus and a Sprouty-related cysteine-rich region (SPR domain) in the C-terminus that is necessary for membrane localization. However, Spred-3 does not possess a functional c-kit binding domain (KBD), since the critical amino acid Arg residue in this region was replaced with Gly in Spred-3. Although Spred-3 suppressed growth factor-induced MAP kinase (Erk) activation, inhibitory activity of Spred-3 was lower than that of Spred-1 or Spred-2. By the analysis of chimeric molecules between Spred-3 and Spred-1, we found that the SPR domain, rather than KBD, is responsible for efficient Erk suppression. The finding of Spred-3 revealed the presence of a novel family of regulators for the Ras/MAP kinase pathway, each member of which may have different specificities for extracellular signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Chromosomes, Human, Pair 19
  • Cloning, Molecular
  • Enzyme Activation
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-kit / metabolism
  • Repressor Proteins / chemistry
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism*
  • Sequence Alignment
  • Tissue Distribution
  • Tyrosine / metabolism


  • Protein Isoforms
  • Repressor Proteins
  • Spred-3 protein, mouse
  • Tyrosine
  • Proto-Oncogene Proteins c-kit
  • Mitogen-Activated Protein Kinases