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      ECRG2 regulates cell migration/invasion through urokinase-type plasmin activator receptor (uPAR)/beta1 integrin pathway.

      The Journal of Biological Chemistry
      Antigens, CD29, genetics, metabolism, Cell Line, Tumor, Cell Movement, Humans, Neoplasms, physiopathology, Protein Binding, Proteinase Inhibitory Proteins, Secretory, Receptors, Urokinase Plasminogen Activator, Signal Transduction, Tumor Suppressor Proteins, Urokinase-Type Plasminogen Activator

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          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.

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