Extracellular calumenin suppresses ERK1/2 signaling and cell migration by protecting fibulin-1 from MMP-13-mediated proteolysis
Extracellular calumenin suppresses ERK1/2 signaling and cell migration by protecting fibulin-1 from MMP-13-mediated proteolysis
复制标题
细胞外 calumenin 通过保护 fibulin-1 免受 MMP-13 介导的蛋白水解作用来抑制 ERK1/2 信号传导和细胞迁移
DOI：
10.1038/onc.2014.52
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发表时间：
2015-02-19
期刊：
影响因子：
8
通讯作者：
Teng, J.
中科院分区：
文献类型：
--
作者：
Wang, Q.;Shen, B.;Teng, J.
Extracellular proteins are vital for cell activities, such as cell migration. Calumenin is highly conserved among eukaryotes, but its functions are largely unclear. Here, we identify extracellular calumenin as a suppressor of cell migration and tumor metastasis. Calumenin binds to and stabilizes fibulin-1, leading to inactivation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling. We further identify the minimal functional domain of calumenin (amino acids 74–138 and 214–280). Depletion of calumenin induces fibulin-1-and phospho-ERK1/2 (pERK1/2)-dependent promotion of cell migration. Consistently, in hepatocellular and pancreatic carcinoma, both calumenin and fibulin-1 are downregulated. Furthermore, we show that matrix metalloproteinase-13 (MMP-13) proteolyzes fibulin-1 and that calumenin protects fibulin-1 from cleavage by MMP-13. Calumenin, together with fibulin-1, also interacts with fibronectin and depends on both syndecan-4 and α5β1-integrin to suppress ERK1/2 signaling and inhibit cell migration. Thus, extracellular calumenin regulates fibulin-1 to have crucial roles in ERK1/2 signaling and cell migration.
