A polymorphic variant of AFAP-110 enhances cSrc activity

David A. Clump, Jing Jie Yu, Young Jin Cho, Rui Gao, John Jett, Henry Zot, Jess M. Cunnick, Brandi Snyder, Anne C. Clump, Melissa Dodrill, Peter Gannett, James E. Coad, Robert Shurina, W. Douglas Figg, Eddie Reed, Daniel C. Flynn

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish
Pages (from-to)276-285
Number of pages10
JournalTranslational Oncology
Issue number4
StatePublished - Aug 2010
Externally publishedYes


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