Abstract
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a widely secreted protein that regulates cell motility, proliferation, and apoptosis. Although it is recognized that TIMP-1–tetraspanin CD63 regulates epithelial cell apoptosis and proliferation, how TIMP-1 controls cell motility is not well understood. In this study, we identify tetraspanin CD82 (also called KAI1) as a component of the promiscuous TIMP-1 interacting protein complex on cell surface of human pancreatic adenocarcinoma cells. CD82 directly binds to TIMP-1 N-terminal region through its large extracellular loop and co-localizes with TIMP-1 in both cancer cell lines and clinical samples. Moreover, CD82 facilitates membrane-bound TIMP-1 endocytosis, which significantly contributes to the anti-migration effect of TIMP-1. CD82 silencing partially eliminates these functions. TIMP-1 and CD82 expression status in patients with pancreatic ductal adenocarcinoma (PDAC) might demonstrate future usefulness as a differentiation marker and give us new insight into tumorigenic metastatic potential.
Highlights
Tissue inhibitors of metalloproteinases (TIMPs) are well known natural inhibitors of matrix metalloproteinases (MMPs); and their regulation of extracellular matrix remodeling is one of the most critical rate-limiting steps in the process of metastasis [1]
To test the possibility of Tissue inhibitor of metalloproteinases-1 (TIMP-1) interacting with other tetraspanins, we used LC-MS/MS to analyze protein complexes co-immunoprecipitated with TIMP-1 [Figure 1a (I)]
Varied signal strength was due to the unequal TIMP-1 and CD82 expression in the cells: they were lowest in MCF-7 cells
Summary
Tissue inhibitors of metalloproteinases (TIMPs) are well known natural inhibitors of matrix metalloproteinases (MMPs); and their regulation of extracellular matrix remodeling is one of the most critical rate-limiting steps in the process of metastasis [1]. The non-covalent binding of TIMPs to MMPs, which are secreted by cells, reverses the unbalanced proteolytic activity of tumors and prevents local cell migration and invasion [2]. Previous studies have demonstrated that TIMP-1 binds a proMMP9/CD44 complex that facilitates erythroid cell survival and is localized to the cell surface [5]. We previously demonstrated that TIMP-1 dramatically inhibited cytokine-induced apoptosis in damage-sensitive rat pancreatic islets. It partially restored glucose-stimulated insulin secretion [6]. TIMP-1 mediated its cell signaling function through an MMP-independent mechanism [8, 9]. Other potential proteins might interact with the TIMP-1/CD63 complex to mediate differential effects on cell growth, intracellular signaling and migration
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