Truncation of annexin A1 is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells
Truncation of annexin A1 is a regulatory lever for linking epidermal growth factor signaling with cytosolic phospholipase A2 in normal and malignant squamous epithelial cells
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DOI：
10.1074/jbc.m707538200
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发表时间：
2007-12-07
影响因子：
4.8
通讯作者：
Huh, Nam-ho
中科院分区：
文献类型：
--
作者：
Sakaguchi, Masakiyo;Murata, Hitoshi;Huh, Nam-ho
调节细胞生长和凋亡是膜联蛋白A1 （ANXA1）的多效功能之一。尽管先前关于ANXA1在许多人类癌症中的过表达以及ANXA1对生长抑制和/或诱导细胞凋亡的报道可能表明了ANXA1的肿瘤抑制性质，但其功能的分子机制在很大程度上仍然未知。在这里，我们提供的证据表明，ANXA1通过与正常人角质形成细胞中的S100A11相互作用，将表皮生长因子触发的生长信号通路与胞质磷脂酶A(2) (cPLA(2))（花生四烯酸级联的一种引发酶）联系起来（NHK）。Ca2+依赖的S100A11与ANXA1的结合促进后者与cPLA2的结合，导致cPLA2活性的抑制，这是NHK生长所必需的。当NHK暴露于表皮生长因子时，ANXA1仅在Trp位点被切割（12），这种切割是由组织蛋白酶d执行的。在鳞状癌细胞中，这一途径被证明是组成性激活的。新发现的机制交集可能是建立对抗人类癌症和其他细胞生长障碍的新措施的有希望的目标。
Regulation of cell growth and apoptosis is one of the pleiotropic functions of annexin A1 (ANXA1). Although previous reports on the overexpression of ANXA1 in many human cancers and on growth suppression and/or induction of apoptosis by ANXA1 may indicate the tumor-suppressive nature of ANXA1, molecular mechanisms of the function of ANXA1 remain largely unknown. Here we provide evidence that ANXA1 mechanistically links the epidermal growth factor-triggered growth signal pathway with cytosolic phospholipase A(2) (cPLA(2)), an initiator enzyme of the arachidonic acid cascade, through interaction with S100A11 in normal human keratinocytes (NHK). Ca2+ -dependent binding of S100A11 to ANXA1 facilitated the binding of the latter to cPLA2, resulting in inhibition of cPLA2 activity, which is essential for the growth of NHK. On exposure of NHK to epidermal growth factor, ANXA1 was cleaved solely at Trp(12), and this cleavage was executed by cathepsin D. In squamous cancer cells, this pathway was shown to be constitutively activated. The newly found mechanistic intersection may be a promising target for establishing new measures against human cancer and other cell growth disorders.