Actin filament-associated protein 1 is required for cSrc activity and secretory activation in the lactating mammary gland.
Actin filament-associated protein 1 is required for cSrc activity and secretory activation in the lactating mammary gland.
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作者：
肌动蛋白促动相关蛋白1（AFAP 1）是cSrc的一种衔接蛋白，其与丝状肌动蛋白结合并调节该酪氨酸激酶的活性以影响肌动蛋白细胞骨架组织的变化。在乳腺癌和前列腺癌细胞中，AFAP 1已被证明可以调节需要肌动蛋白细胞骨架变化的细胞反应，如粘附、侵袭伪足形成和侵袭。然而，AFAP 1的正常生理作用仍然难以捉摸。在这项研究中，我们建立了一个AFAP 1基因敲除小鼠模型，建立了一个新的生理作用AFAP 1在哺乳期。具体而言，这些动物表现出泌乳缺陷，导致无法有效哺乳。在组织学上，哺乳期基因敲除小鼠的乳腺通过肺泡上皮细胞中大的细胞质脂滴的积累来区分。脂质合成和脂肪生成基因的表达减少，而β-酪蛋白（一种乳蛋白）的产生没有相应的减少。此外，这些缺陷与性早熟退化的组织学和生化体征有关。这项研究还表明，AFAP 1通过与cSrc形成复合物并成为酪氨酸磷酸化来响应催乳素（一种催乳激素）。总之，这些观察结果指出了分泌激活的缺陷。该表型的某些特征反映了cSrc基因敲除小鼠分泌激活的缺陷，但最重要的是，AFAP 1敲除小鼠乳腺中cSrc的活性在哺乳早期降低，并且活性cSrc在腔上皮细胞顶端表面的定位在哺乳期间在缺乏AFAP 1的情况下选择性丢失。这些数据首次定义了AFAP 1对正常乳腺中cSrc活性的空间和时间调节的需求，特别是对乳汁生产。
Actin filament-associated protein 1 (AFAP1) is an adaptor protein of cSrc that binds to filamentous actin and regulates the activity of this tyrosine kinase to affect changes to the organization of the actin cytoskeleton. In breast and prostate cancer cells, AFAP1 has been shown to regulate cellular responses requiring actin cytoskeletal changes such as adhesion, invadopodia formation and invasion. However, a normal physiological role for AFAP1 has remained elusive. In this study, we generated an AFAP1 knockout mouse model that establishes a novel physiological role for AFAP1 in lactation. Specifically, these animals displayed a defect in lactation that resulted in an inability to efficiently nurse. Histologically, the mammary glands of the lactating knockout mice were distinguished by the accumulation of large cytoplasmic lipid droplets in the alveolar epithelial cells. There was a reduction in lipid synthesis and the expression of lipogenic genes without a corresponding reduction in the production of beta-casein, a milk protein. Furthermore, these defects were associated with histological and biochemical signs of precocious involution. This study also demonstrated that AFAP1 responds to prolactin, a lactogenic hormone, by forming a complex with cSrc and becoming tyrosine phosphorylated. Together, these observations pointed to a defect in secretory activation. Certain characteristics of this phenotype mirrored the defect in secretory activation in the cSrc knockout mouse, but most importantly, the activity of cSrc in the mammary gland was reduced during early lactation in the AFAP1 null mouse and the localization of active cSrc at the apical surface of luminal epithelial cells during lactation was selectively lost in the absence of AFAP1. These data define, for the first time, the requirement of AFAP1 for the spatial and temporal regulation of cSrc activity in the normal breast, specifically for milk production.
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影响因子：
--
作者：
BERLANGA, JJ;VARA, JAF;GARCIARUIZ, JP
通讯作者：
GARCIARUIZ, JP
影响因子：
8.7
作者：
Liu, Y;Chen, BPC;Shyy, JYJ
通讯作者：
Shyy, JYJ
DOI：
10.1073/pnas.1018861108
发表时间：
2012-02-21
影响因子：
11.1
作者：
Marcotte, Richard;Smith, Harvey W.;Muller, William J.
通讯作者：
Muller, William J.
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
7.8
作者：
Naylor, Matthew J;Li, Na;Cheung, Julia;Lowe, Emma T;Lambert, Elise;Marlow, Rebecca;Wang, Pengbo;Schatzmann, Franziska;Wintermantel, Timothy;Schuetz, Gunther;Clarke, Alan R;Mueller, Ulrich;Hynes, Nancy E;Streuli, Charles H
通讯作者：
Streuli, Charles H