A Polymorphic Variant of AFAP-110 Enhances cSrc Activity

被引：4

作者：

Clump, David A. ^{[1
,2
]}

Yu, Jing Jie ^{[1
,3
]}

Cho, YoungJin ^{[1
,2
]}

Gao, Rui ^{[4
]}

Jett, John ^{[5
]}

Zot, Henry ^{[6
]}

Cunnick, Jess M. ^{[1
,7
]}

Snyder, Brandi ^{[1
,3
]}

Clump, Anne C. ^{[1
,2
]}

Dodrill, Melissa ^{[1
,2
]}

Gannett, Peter ^{[5
]}

Coad, James E. ^{[7
]}

Shurina, Robert ^{[8
]}

Figg, W. Douglas ^{[4
]}

Reed, Eddie ^{[9
]}

Flynn, Daniel C. ^{[1
]}

机构：

[1] W Virginia Univ, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA

[2] W Virginia Univ, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA

[3] W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA

[4] NCI, Mol Pharmacol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA

[5] W Virginia Univ, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA

[6] Univ W Georgia, Dept Biol, Carrollton, GA USA

[7] W Virginia Univ, Dept Pathol, Morgantown, WV 26506 USA

[8] Wheeling Jesuit Univ, Dept Biol, Wheeling, WV USA

[9] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, CoCHP, Atlanta, GA USA

来源：

TRANSLATIONAL ONCOLOGY | 2010年 / 3卷 / 04期

基金：

美国国家卫生研究院;

关键词：

PLECKSTRIN-HOMOLOGY DOMAIN; ACTIN-FILAMENT INTEGRITY; OVARIAN-CANCER CELLS; INOSITOL PHOSPHATES; SIGNALING PROTEINS; TYROSINE KINASE; ACTIVATED SRC; PH DOMAIN; PHOSPHORYLATION; ABILITY;

D O I：

10.1593/tlo.10106

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Enhanced expression and activity of cSrc are associated with ovarian cancer progression. Generally, cSrc does not contain activating mutations; rather, its activity is increased in response to signals that affect a conformational change that releases its auto-inhibition. In this report, we analyzed ovarian cancer tissues for the expression of a cSrc-activating protein, AFAP-110. AFAP-110 activates cSrc through a direct interaction that releases it from its autoinhibited conformation. Immunohistochemical analysis revealed a concomitant increase of AFAP-110 and cSrc in ovarian cancer tissues. An analysis of the AFAP-110 coding sequence revealed the presence of a nonsynonymous, single-nucleotide polymorphism that resulted in a change of Ser403 to Cys403. In cells that express enhanced levels of cSrc, AFAP-110(403C) directed the activation of cSrc and the formation of podosomes independently of input signals, in contrast to wild-type AFAP-110. We therefore propose that, under conditions of cSrc overexpression, the polymorphic variant of AFAP-110 promotes cSrc activation. Further, these data indicate a mechanism by which an inherited genetic variation could influence ovarian cancer progression and could be used to predict the response to targeted therapy.

引用

页码：276 / U93

页数：12

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