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.
Highlights
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
Grb[2] is phosphorylated on tyrosine residue 160 (Y160) by c-Src[18], BCR-Abl[19], fibroblast growth factor receptor 2 (FGFR2)[20], NPM-ALK, TPR-Met and TEL-JAK2. We resolve these elusive roles by demonstrating that Grb[2] is only functional in mitogen-activated protein kinase (MAPK) signal transduction when it is in its monomeric form; and that dissociation of the constitutive dimer is facilitated by either phosphorylation of Y160 or through the binding of a tyrosylphosphate-containing ligand
Our data reveal the presence of high levels of phosphorylation of Y160 (pY160), the monomeric signalling active form of Grb[2], in cancer tissue cells and suggest that this could be a marker for proliferative MAPK activation and resulting oncogenic outcome
Summary
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. Correspondence and requests for materials should be addressed to J.E.L. Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein with no intrinsic enzymatic activity which is ubiquitously expressed in all eukaryotic cells. Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein with no intrinsic enzymatic activity which is ubiquitously expressed in all eukaryotic cells It was originally discovered as epidermal growth factor receptor (EGFR) interacting protein[1] but is known to form complexes with a wide variety of cellular proteins including, but not limited to, protein tyrosine kinases, receptor tyrosine kinases, phosphatases, adaptors and intracellular scaffolds[2,3,4,5,6,7]. We resolve these elusive roles by demonstrating that Grb[2] is only functional in MAPK signal transduction when it is in its monomeric form; and that dissociation of the constitutive dimer is facilitated by either phosphorylation of Y160 (pY160) or through the binding of a tyrosylphosphate-containing ligand. Our data reveal the presence of high levels of pY160, the monomeric signalling active form of Grb[2], in cancer tissue cells and suggest that this could be a marker for proliferative MAPK activation and resulting oncogenic outcome
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