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Extracellular calumenin suppresses ERK1/2 signaling and cell migration by protecting fibulin-1 from MMP-13-mediated proteolysis

Abstract

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.

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Acknowledgements

We thank Dr W Scott Argraves at the Medical University of South Carolina for kindly providing anti-fibulin-1 antibody (3A11). The lentivirus system is a kind gift from Dr Jincai Luo at Peking University. We also thank Dr Li Yu and Dr Xiaofeng Wang at Tsinghua University, and Dr Zhengfan Jiang at Peking University for helpful discussion. We also thank Dr IC Bruce at Zhejiang University and Dr Xiaolei Su at the University of California, San Francisco, for reading the manuscript. This work was supported by the National Natural Science Foundation of China (31271424) and the Major State Basic Research Development Program of China (973 program) (2010CB833705).

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Wang, Q., Shen, B., Chen, L. et al. Extracellular calumenin suppresses ERK1/2 signaling and cell migration by protecting fibulin-1 from MMP-13-mediated proteolysis. Oncogene 34, 1006–1018 (2015). https://doi.org/10.1038/onc.2014.52

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