AFAP-110 is a binding partner for Src and PKC( and affects changes in actin filament integrity as an actin filament cross linking protein and as a cSrc activating protein. This project focuses on the role of AFAP-110 as a modulator of actin filament integrity and cell motility in response to PKC??signaling. Our data support the hypothesis that AFAP-110 relays signals from PKC? that promote (i) actin filament cross linking and (ii) activation of cSrc and downstream signals that regulate actin filament integrity. These two functions are relevant to cell motility, for two reasons. First, actin filament cross linking is required at the leading edge of a cell to provide protrusive force for extension of lamellipodia. Second, cSrc activation results in a loss of actin filament integrity across the cell body which releases the cell from the constraints of its own cytoskeletal architecture for subsequent movement. AFAP-110 cross links F-actin due to the presence of an actin binding domain and its ability to multimerize, while activation of cSrc is attributed to SH3 interactions between these ? two binding partners. AFAP-110 is also a binding partner and substrate for PKC?, in vivo and in vitro. ? Phosphorylation by PKC? reduces the stability and size of AFAP-110 multimers. Like other actin filament cross linking proteins, smaller multimers are able to cross link F-actin more efficiently. AFAP- 110 is also able to modulate activation of cSrc and changes in actin filament integrity in response to PKC??signaling. This project will determine the mechanism by which AFAP-110 relays signals from PKC??that regulate (i) actin filament cross linking, (ii) cSrc activation, (iii) cSrc-associated signals that control actin filament integrity and (iv) cell motility and invasion. As AFAP-110 can modulate signals that affect both cell motility and invasion, AFAP-110 may be a novel biomarker or target for intervention in cancers where PKC( and cSrc are activated, e.g. breast, prostate or colon cancers. ? ?
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| Clump, David A; Yu, Jing Jie; Cho, Youngjin et al. (2010) A Polymorphic Variant of AFAP-110 Enhances cSrc Activity. Transl Oncol 3:276-85 |
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| Guo, Nancy L; Wan, Ying-Wooi; Tosun, Kursad et al. (2008) Confirmation of gene expression-based prediction of survival in non-small cell lung cancer. Clin Cancer Res 14:8213-20 |
