Effect of potent and selective inhibitors of the Grb2 SH2 domain on cell motility.
Cell motility has been correlated both with oncogenic invasiveness and metastatic potential. The development of selective inhibitors of motility has thus great potential importance. Grb2 is a SH2/SH3 domain-containing adaptor protein that links growth factor receptor tyrosine kinases to the Ras signaling pathway. We have developed specific small molecule inhibitors of the Grb2 SH2 domain as potential leads for drug discovery. Synthesis of the inhibitors and their effects on growth factor-induced growth in cells have been reported previously. In the current study, we establish that these inhibitors inhibit hepatocyte growth factor/scatter factor-induced A431 and Madin-Darby canine kidney cell motility and various cell motility-related events, including epidermal growth factor-induced ruffling of A431 cells and epidermal growth factor-induced translocation of the small GTPase Rac in these cells. We demonstrate for the first time a direct role for Grb2 in cell motility and indicate a new avenue for cancer therapeutics.
Gay
B
B
Department of Oncology, Novartis Pharma A.G., CH-4002 Basel, Switzerland. brigitgay@aol.com
Suarez
S
S
Weber
C
C
Rahuel
J
J
Fabbro
D
D
Furet
P
P
Caravatti
G
G
Schoepfer
J
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D004285:Dogs; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D019204:GTP-Binding Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D010455:Peptides / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011994:Recombinant Proteins; D020744:rac GTP-Binding Proteins; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C120804:CGP 78850; C120805:CGP 85793; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010455:Peptides; D011506:Proteins; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins