title: Selective inhibition of growth factor-stimulated mitogenesis by a cell-permeable Grb2-binding peptide.
abstract: The activation of the mitogen-activated protein kinase (MAPK) cascade by a variety of growth factors and other agents is central to a mitogenic response. In the case of polypeptide growth factors such as the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), the steps leading to activation of MAPK require the function of the adaptor protein Grb2 (growth factor receptor binding protein 2), which can bind either directly or indirectly via its Src homology 2 domain to activated receptor tyrosine kinases. A cell-permeable mimetic of the EGF receptor Grb2 binding site has been investigated for its ability to inhibit biological responses stimulated by a variety of growth factors. Pretreatment of cells with this peptide results in the accumulation of the peptide in cells and its association with Grb2. This is associated with a complete inhibition of the mitogenic response stimulated by EGF and PDGF. In contrast, the peptide has no effect on the mitogenic response stimulated by fibroblast growth factor. The peptide could also inhibit the phosphorylation of MAPK stimulated with EGF and PDGF in the absence of an effect on the fibroblast growth factor response. These data demonstrate that cell-permeable mimetics of Src homology 2 binding sites can selectively inhibit growth factor-stimulated mitogenesis, and also directly demonstrate specificity in the coupling of activated receptor tyrosine kinases to the MAPK cascade.
authors.affiliation: Department of Experimental Pathology, United Medical and Dental School, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: E J
authors.initials: EJ
authors.lastname: Williams
authors.forename: D J
authors.initials: DJ
authors.lastname: Dunican
authors.forename: P J
authors.initials: PJ
authors.lastname: Green
authors.forename: F V
authors.initials: FV
authors.lastname: Howell
authors.forename: D
authors.initials: D
authors.lastname: Derossi
authors.forename: F S
authors.initials: FS
authors.lastname: Walsh
authors.forename: P
authors.initials: P
authors.lastname: Doherty
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D015374:Biosensing Techniques; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D006133:Growth Substances / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects*; D018716:Molecular Mimicry; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D012455:Salamandridae; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases