AFAP-110 regulates signals that affect F-actin

描述（由申请人提供）：AFAP-110是Src和PKCalpha的结合伴侣，作为肌动蛋白丝交联蛋白和cSrc激活蛋白影响肌动蛋白丝完整性的变化。我们的数据支持AFAP-110中继来自PKCalpha的信号的假设，所述PKCalpha促进（i）肌动蛋白丝交联和（ii）cSrc的激活。这两种功能与细胞运动性相关，因为在细胞的前缘需要肌动蛋白丝交联以提供用于板状伪足延伸的伸展力，而cSrc活化指导整个细胞体的肌动蛋白丝完整性的损失并刺激促进运动性和侵入的下游信号。AFAP-110交联肌动蛋白丝和激活cSrc的内在能力是响应于PKCalpha信号传导而揭示的。AFAP-110是体内和体外PKCalpha的结合伴侣和底物。与PKCa的相互作用影响AFAP-110的构象变化，促进其交联肌动蛋白丝的能力。PKCalpha活化还指导AFAP-110移动至cSrc并通过SH 3结合活化cSrc。AFAP-110的激活形式可以独立地激活cSrc并促进细胞运动和侵袭。显性负性AFAP-110将阻断PKCa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PKCalpha传递信号的机制，这些信号调节（i）肌动蛋白丝交联，（ii）cSrc激活和（iii）细胞运动和侵袭。这项工作的意义在于：（a）cSrc活化与人类肿瘤中侵袭性表型的获得相关，（B）AFAP-110可活化cSrc并影响细胞运动性和侵袭性，以及（c）PKC α、cSrc和AFAP-110在侵袭性乳腺癌组织和细胞系中上调。因此，AFAP-110可能是一种新的生物标志物或靶点，用于干预PKCalpha和cSrc被激活的浸润性癌症。

DESCRIPTION (provided by applicant): AFAP-110 is a binding partner for Src and PKCalpha 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 PKCalpha 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 PKCalpha signaling. AFAP-110 is a binding partner and substrate for PKCalpha, in vivo and in vitro. Interactions with PKCa affect a conformational change upon AFAP-110 that promotes its ability to cross link actin filaments. PKCalpha 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 PKCalpha-directed cSrc activation and changes in actin filament integrity. This project will determine the mechanism by which AFAP-110 relays signals from PKCalpha 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) PKCa, 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 PKCalpha and cSrc are activated.