The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5

Mol Biol Cell. 1993 Nov;4(11):1175-88. doi: 10.1091/mbc.4.11.1175.

Abstract

Mutations in the Caenorhabditis elegans gene sem-5 affect cell signaling processes involved in guiding a class of cell migrations and inducing vulval cell fates. The sem-5 sequence encodes a protein comprised almost exclusively of SH2 and SH3 domains (SH, src homology region) that are found together in many signaling proteins and nonreceptor tyrosine kinases. A human protein, GRB2, was identified by its ability to associate with the activated human epidermal growth factor receptor (hEGFR). The GRB2 and Sem-5 proteins share an identical architecture of their SH2 and SH3 domains and 58% amino acid sequence identity. Here we demonstrate that GRB2 and a Drosophila sem-5-like gene Drk can specifically rescue sem-5 mutants. We also show that Sem-5, like GRB2, can bind to the activated hEGFR in vitro. We further correlate the abilities of several mutant variants of GRB2 and Sem-5 to bind to the hEGFR in vitro with their abilities to functionally replace sem-5 in vivo. These data indicate that GRB2 and Drk are functional homologues of Sem-5 and demonstrate the high degree of conservation of both structure and function between signaling systems throughout evolution.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans Proteins*
  • Cloning, Molecular
  • Drosophila Proteins*
  • ErbB Receptors / analysis
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Female
  • GRB2 Adaptor Protein
  • Genes, Helminth
  • Genes, Insect / genetics
  • Helminth Proteins / genetics*
  • Humans
  • Insect Hormones / genetics*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Point Mutation / genetics
  • Proteins / genetics*
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / isolation & purification
  • Signal Transduction / genetics*
  • Transformation, Genetic
  • Vulva / growth & development

Substances

  • Adaptor Proteins, Signal Transducing
  • Caenorhabditis elegans Proteins
  • Drosophila Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Helminth Proteins
  • Insect Hormones
  • Proteins
  • Recombinant Fusion Proteins
  • Sem-5 protein, C elegans
  • drk protein, Drosophila
  • ErbB Receptors
  • Receptors, Platelet-Derived Growth Factor