KGF-induced motility of breast cancer cells is dependent on Grb2 and Erk1,2.
Breast cancer metastasis is directly associated with breast cancer cell motility. Using a cell culture wounding model, we have demonstrated that keratinocyte growth factor (KGF) enhanced the motility of estrogen receptor-positive breast cancer cells. However, the mechanisms by which KGF enhanced motility of breast cancer cells are not known. In the present study, we report that KGF-induced motility requires intact tyrosine kinase signaling since genistein, a tyrosine kinase inhibitor, led to decreased motility of breast cancer cells mediated by KGF. Using cDNA microarrays, we previously found that KGF increased the expression of Grb2 mRNA by 2 3-fold. Since Grb2 plays an important role in tyrosine kinase signaling, we examined the involvement of Grb2 in KGF-induced motility. Down-regulation of Grb2 protein expression inhibited KGF-induced motility. Since Grb2 is known to regulate Erk1,2 and Akt kinase activities we determined whether these downstream proteins may be vital to KGF-induced motility. Inhibiting the activation of Erk1,2 by PD98059 suppressed KGF-induced motility whereas inhibiting the activation of Akt by wortmannin did not affect KGF-induced motility. In conclusion, these results indicate that KGF mediated signal transduction employs Grb2 to transduce the tyrosine kinase signals resulting in the activation of Erk1,2 and breast cancer cell motility.
Zang
Xiao-Ping
XP
Department of Pharmaceutical Sciences, University of Oklahoma, Health Sciences Center, Oklahoma City, Oklahoma 73117, USA.
Siwak
Doris R
DR
Nguyen
Thi X
TX
Tari
Ana M
AM
Pento
J Thomas
JT
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000935:Antifungal Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D051380:GRB2 Adaptor Protein; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; C496453:FGF7 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D012333:RNA, Messenger; D051523:Fibroblast Growth Factor 7; C012258:mevastatin; D005346:Fibroblast Growth Factors; D008148:Lovastatin; D019833:Genistein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3