The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling.
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.
Lowenstein
E J
EJ
Department of Pharmacology, New York University Medical Center, New York 10016.
Daly
R J
RJ
Batzer
A G
AG
Li
W
W
Margolis
B
B
Lammers
R
R
Ullrich
A
A
Skolnik
E Y
EY
Bar-Sagi
D
D
Schlessinger
J
J
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002107:Caenorhabditis / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis / Q000302:isolation & purification; D066246:ErbB Receptors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D051379:Mice; D008845:Microinjections; D008969:Molecular Sequence Data; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor; D016415:Sequence Alignment; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D011956:Receptors, Cell Surface; D004247:DNA; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D015689:Oncogene Protein p21(ras)