The SH2 and SH3 Domain-Containing Protein GRB2 Links Receptor Tyrosine Kinases to Ras Signaling

Cell. 1992 Aug 7;70(3):431-42. doi: 10.1016/0092-8674(92)90167-b.

Abstract

A cDNA clone encoding a novel, widely expressed protein (called growth factor receptor-bound protein 2 or GRB2) containing one src homology 2 (SH2) domain and two SH3 domains was isolated. Immunoblotting experiments indicate that GRB2 associates with tyrosine-phosphorylated epidermal growth factor receptors (EGFRs) and platelet-derived growth factor receptors (PDGFRs) via its SH2 domain. Interestingly, GRB2 exhibits striking structural and functional homology to the C. elegans protein sem-5. It has been shown that sem-5 and two other genes called let-23 (EGFR like) and let-60 (ras like) lie along the same signal transduction pathway controlling C. elegans vulval induction. To examine whether GRB2 is also a component of ras signaling in mammalian cells, microinjection studies were performed. While injection of GRB2 or H-ras proteins alone into quiescent rat fibroblasts did not have mitogenic effect, microinjection of GRB2 together with H-ras protein stimulated DNA synthesis. These results suggest that GRB2/sem-5 plays a crucial role in a highly conserved mechanism for growth factor control of ras signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blotting, Northern
  • Blotting, Western
  • Caenorhabditis / genetics
  • Cell Line
  • DNA / biosynthesis
  • DNA / isolation & purification
  • ErbB Receptors / metabolism*
  • GRB2 Adaptor Protein
  • Humans
  • Mice
  • Microinjections
  • Molecular Sequence Data
  • Oncogene Protein p21(ras) / metabolism*
  • Phosphorylation
  • Platelet-Derived Growth Factor / metabolism
  • Protein-Tyrosine Kinases / metabolism*
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism
  • Receptors, Cell Surface / metabolism*
  • Receptors, Platelet-Derived Growth Factor
  • Sequence Alignment
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Platelet-Derived Growth Factor
  • Proteins
  • Receptors, Cell Surface
  • DNA
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor
  • Oncogene Protein p21(ras)

Associated data

  • GENBANK/L05499
  • GENBANK/M87278
  • GENBANK/M94130
  • GENBANK/M94264
  • GENBANK/M96995
  • GENBANK/S72766
  • GENBANK/S72767
  • GENBANK/S72768
  • GENBANK/S72769
  • GENBANK/S72771