title: Grb2 monomer-dimer equilibrium determines normal versus oncogenic function.
abstract: The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression.
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Zamal
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Timsah
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Kin M
authors.initials: KM
authors.lastname: Suen
authors.affiliation: Department of Chemistry, Rice University, Houston, Texas 77005, USA.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Cook
authors.affiliation: Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Lee
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Chi-Chuan
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Veterinary Medicine and Surgery, University of Texas, M.D. Anderson Cancer Center, Unit 63, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.affiliation: Department of Chemistry, Rice University, Houston, Texas 77005, USA.
authors.forename: Angel A
authors.initials: AA
authors.lastname: Marti
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Center for Biomolecular Structure and Function, University of Texas, M.D. Anderson Cancer Center, Unit 1000, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D055503:Protein Multimerization; D015398:Signal Transduction; D020664:Son of Sevenless Proteins / Q000378:metabolism; D046888:Tissue Array Analysis; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020664:Son of Sevenless Proteins; D014443:Tyrosine