title: Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling.
abstract: The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19(Arf), Trp53 and p21(Cdkn1a). In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19(Arf), Trp53, p21(Cdkn1a) and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.
authors.affiliation: Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kitajima
authors.forename: T
authors.initials: T
authors.lastname: Miki
authors.forename: Y
authors.initials: Y
authors.lastname: Takegami
authors.forename: Y
authors.initials: Y
authors.lastname: Kido
authors.forename: M
authors.initials: M
authors.lastname: Noda
authors.forename: E
authors.initials: E
authors.lastname: Hara
authors.forename: A
authors.initials: A
authors.lastname: Shamma
authors.forename: C
authors.initials: C
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C492025:Reck protein, mouse; C404992:Spry2 protein, rat; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D066246:ErbB Receptors; C515905:Pak1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases