AFAP-110 is a binding partner for Src and PKCc_ and affects changes in actin filament integrity as an actin filament cross linking protein and as a cSrc activating protein. Our data support the hypothesis that AFAP-110 relays signals from PKCc_ that promote (i) actin filament cross linking and (ii) activation of cSrc. These two functions are relevant to cell motility as actin filament cross linking is required at the leading edge of a cell to provide protrusive force for extension of lamellipodia, while cSrc activation directs a loss of actin filament integrity across the cell body and stimulates downstream signals that promote motility and invasion. The intrinsic ability of AFAP-110 to cross link actin filaments and activate cSrc is revealed in response to PKCc_ signaling. AFAP-110 is a binding partner and substrate for PKCc_, in vivo and in vitro. Interactions with PKCc_ affect a conformational change upon AFAP-110 that promotes its ability to cross link actin filaments. PKCa activation also directs AFAP-110 to move to and activate cSrc through SH3 binding. Activated forms of AFAP-110 can independently activate cSrc and promote cell motility and invasion. Dominant-negative AFAP-110 will block PKCcx-directed cSrc activation and changes in actin filament integrity. This project will determine the mechanism by which AFAP-110 relays signals from PKCc_ that regulate (i) actin filament cross linking, (ii) cSrc activation and (iii) cell motility and invasion. The significance of this work is that (a) cSrc activation correlates with acquisition of the invasive phenotype in human tumors, (b) AFAP-110 can activate cSrc and affect both cellular motility and invasion and (c) PKC_x, cSrc and AFAP-110 are upregulated in breast cancer tissues and cell lines that are invasive. Thus, AFAP- 110 may be a novel biomarker or target for intervention in invasive cancers where PKCoc and cSrc are activated.
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