title: EGFR-AKT-mTOR activation mediates epiregulin-induced pleiotropic functions in cultured osteoblasts.
abstract: Epidermal growth factor (EGF) receptor (EGFR) emerges as an essential molecule for the regulating of osteoblast cellular functions. In the current study, we explored the effect of epiregulin, a new EGFR ligand, on osteoblast functions in vitro, and studied the underlying mechanisms. We found that epiregulin-induced EGFR activation in both primary osteoblasts and osteoblast-like MC3T3-E1 cells. Meanwhile, epiregulin activated AKT-mammalian target of rapamycin (mTOR) and Erk-mitogen-activated protein kinase (MAPK) signalings in cultured osteoblasts, which were blocked by EGFR inhibitor AG1478 or monoclonal antibody against EGFR (anti-EGFR). Further, in primary and MC3T3-E1 osteoblasts, epiregulin promoted cell proliferation and increased alkaline phosphatase activity, while inhibiting dexamethasone (Dex)-induced cell death. Such effects by epiregulin were largely inhibited by AG1478 or anti-EGFR. Notably, AKT-mTOR inhibitors, but not Erk inhibitors, alleviated epiregulin-induced above pleiotropic functions in osteoblasts. Meanwhile, siRNA depletion of Sin1, a key component of mTOR complex 2 (mTORC2), also suppressed epiregulin-exerted effects in MC3T3-E1 cells. Together, these results suggest that epiregulin-induced pleiotropic functions in cultured osteoblasts are mediated through EGFR-AKT-mTOR signalings.
authors.affiliation: The Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, 6 North Hai-er-xiang Road, Nantong, 226001, Jiangsu, People's Republic of China.
authors.forename: Jian-Bo
authors.initials: JB
authors.lastname: Fan
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Xin-Hui
authors.initials: XH
authors.lastname: Zhu
authors.forename: Kun
authors.initials: K
authors.lastname: Yuan
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Xu
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Chen
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Cui
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066260:Epiregulin / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing
chemical_list: D000469:Alkaline Phosphatase; D002352:Carrier Proteins; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D066260:Epiregulin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D058570:TOR Serine-Threonine Kinases; D020032:Tyrphostins; C561937:Mapkap1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; C101044:RTKI cpd; C546843:mTOR protein, mouse; C541485:EGFR protein, mouse