A Polymorphic Variant of AFAP-110 Enhances cSrc Activity.
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-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 amechanismby which an inherited genetic variation could influence ovarian cancer progression and could be used to predict the response to targeted therapy.
Clump
David A
DA
The Mary Babb Randolph Cancer Center and the Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, USA.
Yu
Jing Jie
JJ
Cho
Youngjin
Y
Gao
Rui
R
Jett
John
J
Zot
Henry
H
Cunnick
Jess M
JM
Snyder
Brandi
B
Clump
Anne C
AC
Dodrill
Melissa
M
Gannett
Peter
P
Coad
James E
JE
Shurina
Robert
R
Figg
W Douglas
WD
Reed
Eddie
E
Flynn
Daniel C
DC