title: Tissue kallikrein mediates neurite outgrowth through epidermal growth factor receptor and flotillin-2 pathway in vitro.
abstract: Tissue kallikrein (TK) was previously shown to take most of its biological effects through bradykinin receptors. In this study, we assumed that TK mediated neurite outgrowth was independent of bradykinin receptors. To test the hypothesis, we investigated TK-induced neurite outgrowth and its signaling mechanisms in cultured primary neurons and human SH-SY5Y cells. We found that TK stimulation could increase the number of processes and mean process length of primary neurons, which were blocked by epidermal growth factor receptor (EGFR) inhibitor or down-regulation, small interfering RNA for flotillin-2 and extracellular signal-regulated kinase (ERK) 1/2 inhibitor. Moreover, TK-induced neurite outgrowth was associated with EGFR and ERK1/2 activation, which were inhibited by EGFR antagonist or RNA interference and flotillin-2 knockdown. Interestingly, inhibition of bradykinin receptors had no significant effects on EGFR and ERK1/2 phosphorylation. In the present research, our data also suggested that EGFR and flotillin-2 formed constitutive complex that translocated to around the nuclei in the TK stimulation. In sum, our findings provided evidence that TK could promote neurite outgrowth via EGFR, flotillin-2 and ERK1/2 signaling pathway in vitro.
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No.12 Mid. Wulumuqi Road, Shanghai 200040, PR China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No.12 Mid. Wulumuqi Road, Shanghai 200040, PR China.
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Shanghai 200437, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Shanghai 200437, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, No.110 Ganhe Road, Shanghai 200437, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, No.12 Mid. Wulumuqi Road, Shanghai 200040, PR China. Electronic address: qiang_dong163@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020840:Tissue Kallikreins / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; D020032:Tyrphostins; C106354:flotillins; C101044:RTKI cpd; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020840:Tissue Kallikreins
keywords: B1 bradykinin receptor; B1R; B2 bradykinin receptor; B2R; BK; DIV; EGFR; ERK; Epidermal growth factor receptor; Extracellular signal-regulated kinase; Flot; Flotillin-2; KKS; Neurite outgrowth; PAR; TK; Tissue kallikrein; bradykinin; days in vitro; epidermal growth factor receptor; extracellular signal-regulated kinase; flotillin; kallikrein–kinin system; proteinase-activated receptor; tissue kallikrein