The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase

被引：69

作者：

Ochel, HJ ^{[1
]}

Schulte, TW ^{[1
]}

Nguyen, P ^{[1
]}

Trepel, J ^{[1
]}

Neckers, L ^{[1
]}

机构：

[1] NCI, Med Branch, NIH, Rockville, MD 20850 USA

来源：

MOLECULAR GENETICS AND METABOLISM | 1999年 / 66卷 / 01期

基金：

美国国家卫生研究院;

关键词：

FAK; hsp90; geldanamycin; proteolysis;

D O I：

10.1006/mgme.1998.2774

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

FAK is a nonreceptor tyrosine kinase involved in adhesion-mediated signal transduction whose level of expression Is related to the invasiveness of malignant tumors, In seeking strategies to downregulate FAK, we treated various cell lines in vitro with the benzoquinone ansamycin geldanamycin (GA) which was previously described as a tyrosine kinase inhibitor, but recently has been shown to exert its effects by interfering with the chaperone function of members of the hsp90 family of heat-shock proteins, We evaluated the effects of benzoquinone ansamycins on FAK steady-state protein level and FAR half-life in breast and prostate carcinoma, Ewing's sarcoma, and 3T3 fibroblasts, Our data demonstrate that GA stimulates the proteolytic degradation of FAK in all cell lines examined and markedly reduces the half-life of newly synthesized FAR protein without significantly altering the level of FAK mRNA. These data demonstrate FAR to be another tyrosine kinase sensitive to the destabilizing effects of benzoquinone ansamycins and further show that small molecule-mediated pharmacologic modulation of FAR protein level is a feasible approach to the interdiction of FAK function.

引用

页码：24 / 30

页数：7

共 47 条

[1] FOCAL ADHESION KINASE (P125(FAK)) EXPRESSION CORRELATES WITH MOTILITY OF HUMAN-MELANOMA CELL-LINES [J].