Abstract
ECRG2 is a novel gene that shows sequence similarity to KAZAL-type serine protease inhibitor. We have previously demonstrated that ECRG2 inhibits migration/invasion of lung cancer PG cells. However, the mechanism by which ECRG2 performs these activities is a compelling question. Urokinase-type plasmin activator (uPA) binding to uPAR induces migration/invasion through multiple interactors including integrins. In this study, we found that ECRG2 binds specifically to the kringle domain of uPA. Moreover, we demonstrated that ECRG2 forms a complex with uPA.uPAR, that such a complex modifies the dynamical association of uPAR with beta1 integrins, and that disruption inhibits Src/MAP (mitogen-activated protein) kinase pathway, resulting in suppression of cell migration/invasion in an in vitro Matrigel migration/invasion assay. Conversely, depletion of ECRG2 markedly enhanced the association of uPAR with beta1 integrins, elevated basal Src/MAP kinase activation, and stimulated HT1080, MDA-MB-231, and MCF-7 cell migration/invasion. Together, our results provide evidence that ECRG2 is involved in the regulation of migration/invasion through uPA/uPAR/beta1 integrins/Src/MAP kinase pathway and may represent a novel therapeutic target for cancer.
Highlights
Tumor cells must invade through the adjacent basement membrane into surrounding tissues and migrate to and invade the vasculature to metastasize to distant sites (1)
We demonstrate that the direct binding of esophageal cancer-related gene 2 (ECRG2) to urokinase-type plasminogen activator (uPA) present in the uPA1⁄7uPAR complex disrupts the association of uPA1⁄7uPA receptor (uPAR) with 1 integrins, leading to reduced activation of the Src/MAP kinase pathway, resulting in abatement of uPA signaling through the uPAR1⁄71 integrins complex
Identification of ECRG2-binding Sequence in uPA—Previous observations have demonstrated that ECRG2 physically interacts with uPA (10). uPA consists of two disulfide bridge-linked polypeptide chains: the N-terminal polypeptide containing a uPA growth factor-like domain (Fig. 1A, GFD), a kringle domain, and a linked or connecting peptide region and a large C-terminal, serine protease polypeptide (21)
Summary
Tumor cells must invade through the adjacent basement membrane into surrounding tissues and migrate to and invade the vasculature to metastasize to distant sites (1). We demonstrated that ECRG2 forms a complex with uPA1⁄7uPAR, that such a complex modifies the dynamical association of uPAR with 1 integrins, and that disruption inhibits Src/MAP (mitogen-activated protein) kinase pathway, resulting in suppression of cell migration/invasion in an in vitro Matrigel migration/invasion assay. Our results provide evidence that ECRG2 is involved in the regulation of migration/invasion through uPA/uPAR/1 integrins/Src/MAP kinase pathway and may represent a novel therapeutic target for cancer.
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