title: A brain-specific Grb2-associated regulator of extracellular signal-regulated kinase (Erk)/mitogen-activated protein kinase (MAPK) (GAREM) subtype, GAREM2, contributes to neurite outgrowth of neuroblastoma cells by regulating Erk signaling.
abstract: Grb2-associated regulator of Erk/MAPK1 (GAREM) is an adaptor molecule in the EGF-mediated signaling pathway. GAREM is expressed ubiquitously in human organs and cultured cells. Two GAREM homologues are encoded by the human genome. Therefore, previously identified GAREM is named GAREM1. Here we characterized a new subtype of GAREM, GAREM2, that is specifically expressed in the mouse, rat, and human brain. Three GAREM2 tyrosines (Tyr-102, Tyr-429, and Tyr-551) are phosphorylated upon EGF stimulation and are necessary for binding to Grb2. Furthermore, GAREM2 and Shp2 regulate Erk activity in EGF-stimulated cells. These characteristics are similar to those of GAREM1. GAREM2 is expressed in some neuroblastoma cell lines and is also tyrosine-phosphorylated and bound to Grb2 after treatment with EGF. Eventually, GAREM2 regulates Erk activation in the presence of EGF or insulin like growth factor 1. GAREM2 also regulates insulin-like growth factor 1-induced neuronal differentiation of the SH-SY5Y neuroblastoma cell line. Although the structure and function of both GAREM subtypes are similar, GAREM1 is recruited into the nucleus and GAREM2 is not. Nuclear localization of GAREM1 might be controlled by a GAREM1-specific nuclear localization sequence and 14-3-3ε binding. The N-terminal 20 amino acids of GAREM1 make up its nuclear localization sequence that is also a 14-3-3ε binding site. The GAREM family is a new class of adaptor molecules with subtype-specific biological functions.
authors.affiliation: From the Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tanaka
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ishii
authors.forename: Miyuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujitani
authors.forename: Ayusa
authors.initials: A
authors.lastname: Sugeo
authors.forename: Shuhei
authors.initials: S
authors.lastname: Gotoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohta
authors.forename: Mineyoshi
authors.initials: M
authors.lastname: Hiyoshi
authors.forename: Hideki
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Konishi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D017386:Sequence Homology, Amino Acid
chemical_list: C543678:GAREM1 protein, human; D051380:GRB2 Adaptor Protein; D020033:Protein Isoforms; D004815:Epidermal Growth Factor
keywords: Adaptor Proteins; ERK; Epidermal Growth Factor Receptor (EGFR); MAP Kinases (MAPKs); Neurite Outgrowth; Nuclear Translocation