ECRG2 regulates cell migration/invasion through urokinase-type plasmin activator receptor (uPAR)/beta1 integrin pathway.
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.
Cheng
Xiaolong
X
Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
Shen
Zheng
Z
Yin
Litian
L
Lu
Shih-Hsin
SH
Cui
Yongping
Y
D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011485:Protein Binding; D053491:Proteinase Inhibitory Proteins, Secretory; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D000074162:Serine Peptidase Inhibitors, Kazal Type; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D019012:Integrin beta1; D053491:Proteinase Inhibitory Proteins, Secretory; D055293:Receptors, Urokinase Plasminogen Activator; C473799:SPINK7 protein, human; D000074162:Serine Peptidase Inhibitors, Kazal Type; D025521:Tumor Suppressor Proteins; D014568:Urokinase-Type Plasminogen Activator