KGF-induced Motility of Breast Cancer Cells is Dependent on Grb2 and Erk1,2

Overview

Journal Clin Exp Metastasis

Specialty Oncology

Date 2005 Jan 28

PMID 15672868

Citations 9

Authors

Xiao-Ping Zang

Doris R Siwak

Thi X Nguyen

Ana M Tari

J Thomas Pento

Affiliations

Soon will be listed here.

Abstract

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.

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References

Verbeek B, Rijksen G, Vroom T . Grb2 overexpression in nuclei and cytoplasm of human breast cells: a histochemical and biochemical study of normal and neoplastic mammary tissue specimens. J Pathol. 1997; 183(2):195-203. DOI: 10.1002/(SICI)1096-9896(199710)183:2<195::AID-PATH901>3.0.CO;2-Y. View

Lowenstein E, Daly R, Batzer A, Li W, Margolis B, Lammers R . The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992; 70(3):431-42. DOI: 10.1016/0092-8674(92)90167-b. View

Mohammadi M, Honegger A, Rotin D, Fischer R, Bellot F, Li W . A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1. Mol Cell Biol. 1991; 11(10):5068-78. PMC: 361508. DOI: 10.1128/mcb.11.10.5068-5078.1991. View

Stark Jr W, Blaskovich M, Johnson B, Qian Y, Vasudevan A, Pitt B . Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells. Am J Physiol. 1998; 275(1):L55-63. DOI: 10.1152/ajplung.1998.275.1.L55. View

Mason I, Smith R, Dickson C . FGF-7 (keratinocyte growth factor) expression during mouse development suggests roles in myogenesis, forebrain regionalisation and epithelial-mesenchymal interactions. Mech Dev. 1994; 45(1):15-30. DOI: 10.1016/0925-4773(94)90050-7. View

Warne P, Viciana P, Downward J . Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993; 364(6435):352-5. DOI: 10.1038/364352a0. View

Simon M, Bowtell D, Dodson G, Laverty T, Rubin G . Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase. Cell. 1991; 67(4):701-16. DOI: 10.1016/0092-8674(91)90065-7. View

Ulich T, Yi E, Cardiff R, Yin S, Bikhazi N, Biltz R . Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor. Am J Pathol. 1994; 144(5):862-8. PMC: 1887355. View

Gillis P, Savla U, Volpert O, Jimenez B, Waters C, Panos R . Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function. J Cell Sci. 1999; 112 ( Pt 12):2049-57. DOI: 10.1242/jcs.112.12.2049. View

10.

Pei Z, Maloney J, Yang L, Williamson J . A new function for phospholipase C-gamma1: coupling to the adaptor protein GRB2. Arch Biochem Biophys. 1997; 345(1):103-10. DOI: 10.1006/abbi.1997.0245. View

11.

Celli G, LaRochelle W, Mackem S, Sharp R, Merlino G . Soluble dominant-negative receptor uncovers essential roles for fibroblast growth factors in multi-organ induction and patterning. EMBO J. 1998; 17(6):1642-55. PMC: 1170512. DOI: 10.1093/emboj/17.6.1642. View

12.

Tari A, Hung M, Li K, Lopez-Berestein G . Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells. Oncogene. 1999; 18(6):1325-32. DOI: 10.1038/sj.onc.1202422. View

13.

Zang X, Lerner M, Dunn S, Brackett D, Pento J . Antisense KGFR oligonucleotide inhibition of KGF-induced motility in breast cancer cells. Anticancer Res. 2004; 23(6C):4913-9. View

14.

Koos R, Banks P, Inkster S, Yue W, Brodie A . Detection of aromatase and keratinocyte growth factor expression in breast tumors using reverse transcription-polymerase chain reaction. J Steroid Biochem Mol Biol. 1993; 45(4):217-25. DOI: 10.1016/0960-0760(93)90335-t. View

15.

Rozakis-Adcock M, Fernley R, Wade J, Pawson T, Bowtell D . The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature. 1993; 363(6424):83-5. DOI: 10.1038/363083a0. View

16.

Endo A, Kuroda M, Tanzawa K . Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 1976; 72(2):323-6. DOI: 10.1016/0014-5793(76)80996-9. View

17.

Shono T, Kanetake H, Kanda S . The role of mitogen-activated protein kinase activation within focal adhesions in chemotaxis toward FGF-2 by murine brain capillary endothelial cells. Exp Cell Res. 2001; 264(2):275-83. DOI: 10.1006/excr.2001.5154. View

18.

Chandrasekher G, Kakazu A, Bazan H . HGF- and KGF-induced activation of PI-3K/p70 s6 kinase pathway in corneal epithelial cells: its relevance in wound healing. Exp Eye Res. 2001; 73(2):191-202. DOI: 10.1006/exer.2001.1026. View

19.

Bansal G, Cox H, Marsh S, Gomm J, Yiangou C, Luqmani Y . Expression of keratinocyte growth factor and its receptor in human breast cancer. Br J Cancer. 1997; 75(11):1567-74. PMC: 2223534. DOI: 10.1038/bjc.1997.269. View

20.

Clark S, Stern M, Horvitz H . C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains. Nature. 1992; 356(6367):340-4. DOI: 10.1038/356340a0. View