AFAP-110 regulates signals that affect F-actin

AFAP-110是Src和PKCc_的结合伴侣，并影响肌动蛋白丝完整性的变化， 丝交联蛋白和cSrc激活蛋白。我们的数据支持AFAP-110 传递来自PKC_的信号，其促进（i）肌动蛋白丝交联和（ii）cSrc的活化。这两 这些功能与细胞运动有关，因为在细胞的前缘需要肌动蛋白丝交联， 为板状伪足的延伸提供扩张力，而cSrc的激活指导肌动蛋白丝的损失 它可以促进整个细胞体的完整性，并刺激下游信号，促进运动和入侵。的 AFAP-110交联肌动蛋白丝和激活cSrc内在能力被揭示为对PKCc_ 发信号。AFAP-110在体内和体外都是PKC α的结合伴侣和底物。与PKCc的互动_ 影响AFAP-110的构象变化，促进其交联肌动蛋白丝的能力。PKCa 激活还指导AFAP-110移动到cSrc并通过SH 3结合激活cSrc。活化形式 AFAP-110可独立激活cSrc并促进细胞运动和侵袭。显性阴性 AFAP-110将阻断PKCcx指导的cSrc激活和肌动蛋白丝完整性的变化。该项目将 确定AFAP-110从PKC_传递信号调节（i）肌动蛋白丝交叉的机制 连接，（ii）cSrc激活和（iii）细胞运动性和侵袭。这项工作的意义在于（a）cSrc 活化与人肿瘤中侵袭性表型的获得相关。（B）AFAP-110可以活化 （c）PKC_x、cSrc和AFAP-110在乳腺癌中上调， 癌组织和细胞系是侵袭性的。因此，AFAP- 110可能是一种新的生物标志物或靶点， 在PKCoc和cSrc被激活的浸润性癌症中的干预。

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.