title: GAREM, a novel adaptor protein for growth factor receptor-bound protein 2, contributes to cellular transformation through the activation of extracellular signal-regulated kinase signaling.
abstract: Adaptor proteins for the various growth factor receptors play a crucial role in signal transduction through tyrosine phosphorylation. Several candidates for adaptor proteins with potential effects on the epidermal growth factor (EGF) receptor-mediated signaling pathway have been identified by recent phosphoproteomic studies. Here, we focus on a novel protein, GAREM (Grb2-associated and regulator of Erk/MAPK) as a downstream molecule of the EGF receptor. GAREM is phosphorylated at tyrosine 105 and 453 after EGF stimulation. Grb2 was identified as its binding partner, and the proline-rich motifs of GAREM are recognized by the N- and C-terminal SH3 domains of Grb2. In addition, the tyrosine phosphorylations of GAREM are necessary for its binding to Grb2. Because the amino acid sequence surrounding tyrosine 453 is similar to the immunoreceptor tyrosine-based inhibitory motif, Shp2, a positive regulator of Erk, binds to GAREM in this phosphorylation-dependent manner. Consequently, Erk activation in response to EGF stimulation is regulated by the expression of GAREM in COS-7 and HeLa cells, which occurs independent of the presence of other binding proteins, such as Gab1 and SOS, to the activated EGF receptor. Furthermore, the expression of GAREM has an effect on the transformation activity of cultured cells. Together, these findings suggest that GAREM plays a key role in the ligand-mediated signaling pathway of the EGF receptor and the tumorigenesis of cells.
authors.affiliation: Division of Disease Proteomics, Institute for Enzyme Research, the University of Tokushima, Tokushima 770-8503, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Tashiro
authors.forename: Takumi
authors.initials: T
authors.lastname: Tsunematsu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Okubo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohta
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sano
authors.forename: Emiko
authors.initials: E
authors.lastname: Yamauchi
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Konishi
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
chemical_list: C543678:GAREM1 protein, human; D051380:GRB2 Adaptor Protein; D014443:Tyrosine; D011392:Proline; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11