Chang C.-C.Yang M.-H.BEEN-REN LINChen S.-T.SZU-HUA PANHsiao M.Lai T.-C.SZE-KWAN LINYUNG-MING JENGCHIA-YU CHUChen R.-H.PAN-CHYR YANGEugene Chin Y.Kuo M.-L.2019-12-042019-12-0420131350-9047https://www.scopus.com/inward/record.uri?eid=2-s2.0-84873709117&doi=10.1038%2fcdd.2012.136&partnerID=40&md5=c42b79cb9310d665d0ddb133621eb505https://scholars.lib.ntu.edu.tw/handle/123456789/434926CCN family protein 2 (CCN2), also known as connective tissue growth factor, is a secreting protein that modulates multiple cellular events. We previously demonstrated the metastasis-suppressive effect of CCN2 in lung cancer cells. In this study, we investigate the role of CCN2 in anoikis, a form of programmed cell death that is critical in suppressing cancer metastasis. CCN2 binds to the epidermal growth factor receptor (EGFR) and triggers ubiquitination by inhibiting the formation of the β-pix/Cbl complex, resulting in the degradation of EGFR. Binding of CCN2 to EGFR suppresses the phosphorylation of c-Src and extracellular signal-regulated kinase but increases the expression of death-associated protein kinase, which leads to anoikis. Overall, our findings provide evidence validating the use of CCN2 as an anti-metastatic therapy in lung cancer patients, and prospect a potential therapeutic synergy between CCN2 and the anti-EGFR antibody for the treatment of lung cancer. ? 2013 Macmillan Publishers Limited All rights reserved.[SDGs]SDG3Cbl protein; cetuximab; connective tissue growth factor; death associated protein kinase; epidermal growth factor receptor; mitogen activated protein kinase; p21 activated kinase interacting exchange factor; phosphatidylinositol 3 kinase; protein; protein kinase B; protein tyrosine kinase; unclassified drug; anoikis; article; cancer cell; carboxy terminal sequence; complex formation; controlled study; drug potentiation; human; human cell; lung cancer; metastasis inhibition; molecular model; priority journal; protein binding; protein degradation; protein domain; protein function; protein phosphorylation; ubiquitinationjournal article10.1038/cdd.2012.136231751852-s2.0-84873709117