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PMID:19509291

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Citation

Tashiro, K, Tsunematsu, T, Okubo, H, Ohta, T, Sano, E, Yamauchi, E, Taniguchi, H and Konishi, H (2009) 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. J. Biol. Chem. 284:20206-14

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.

Links

PubMed PMC2740447 Online version:10.1074/jbc.M109.021139

Keywords

Amino Acid Motifs; Animals; Binding Sites; COS Cells; Cercopithecus aethiops; Extracellular Signal-Regulated MAP Kinases/metabolism; GRB2 Adaptor Protein/analysis; GRB2 Adaptor Protein/genetics; GRB2 Adaptor Protein/metabolism; Gene Expression; HeLa Cells; Humans; Molecular Sequence Data; Phosphorylation; Proline/chemistry; Proline/metabolism; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism; Receptor, Epidermal Growth Factor/metabolism; Tyrosine/metabolism; src Homology Domains

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H706

F

Seeded From UniProt

complete

HUMAN:GRB2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H706

F

Seeded From UniProt

complete

HUMAN:GRB2

enables

GO:0017124: SH3 domain binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PTN11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9H706

F

Seeded From UniProt

complete

HUMAN:GARE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q06124

F

Seeded From UniProt

complete

HUMAN:GARE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P62993

F

Seeded From UniProt

complete

HUMAN:GARE1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:GARE1

involved_in

GO:0007173: epidermal growth factor receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GARE1

located_in

GO:0005886: plasma membrane

ECO:0000303: author statement without traceable support used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GARE1

involved_in

GO:0008284: positive regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GARE1

enables

GO:0070064: proline-rich region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GARE1

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GARE1

involved_in

GO:0071364: cellular response to epidermal growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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