TY - JOUR
T1 - A polymorphic variant of AFAP-110 enhances cSrc activity
AU - Clump, David A.
AU - Yu, Jing Jie
AU - Cho, Young Jin
AU - Gao, Rui
AU - Jett, John
AU - Zot, Henry
AU - Cunnick, Jess M.
AU - Snyder, Brandi
AU - Clump, Anne C.
AU - Dodrill, Melissa
AU - Gannett, Peter
AU - Coad, James E.
AU - Shurina, Robert
AU - Figg, W. Douglas
AU - Reed, Eddie
AU - Flynn, Daniel C.
N1 - Funding Information:
Address all correspondence to: Daniel C. Flynn, PhD, The Commonwealth Medical College, 501 Madison Ave, Scranton, PA 18510. E-mail: [email protected] 1This work was supported by grants from the National Institutes of Health (CA60731 and RR16440), the Pardee Foundation (D.C.F.), and the West Virginia University Medical Scientists Training Program (D.A.C.). The authors declare no conflict of interest. 2This article refers to supplementary materials, which are designated by Tables W1 and W2 and Figure W1 and are available online at www.transonc.com. 3Current address: University of Pittsburgh Medical Center, Radiation Oncology, 5230 Centre Ave, Pittsburgh, PA 15231. 4Current address: The Commonwealth Medical College, 501 Madison Ave, Scranton, PA 18510. Received 7 January 2010; Revised 18 March 2010; Accepted 31 March 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1944-7124/10/$25.00 DOI 10.1593/tlo.10106
PY - 2010/8
Y1 - 2010/8
N2 - 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 autoinhibition. 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-110403C 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 amechanismby which an inherited genetic variation could influence ovarian cancer progression and could be used to predict the response to targeted therapy.
AB - 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 autoinhibition. 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-110403C 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 amechanismby which an inherited genetic variation could influence ovarian cancer progression and could be used to predict the response to targeted therapy.
UR - http://www.scopus.com/inward/record.url?scp=77955680527&partnerID=8YFLogxK
U2 - 10.1593/tlo.10106
DO - 10.1593/tlo.10106
M3 - Article
AN - SCOPUS:77955680527
SN - 1936-5233
VL - 3
SP - 276
EP - 285
JO - Translational Oncology
JF - Translational Oncology
IS - 4
ER -