title: Signaling adaptor ShcD suppresses extracellular signal-regulated kinase (Erk) phosphorylation distal to the Ret and Trk neurotrophic receptors.
abstract: Proteins of the Src homology and collagen (Shc) family are typically involved in signal transduction events involving Ras/MAPK and PI3K/Akt pathways. In the nervous system, they function proximal to the neurotrophic factors that regulate cell survival, differentiation, and neuron-specific characteristics. The least characterized homolog, ShcD, is robustly expressed in the developing and mature nervous system, but its contributions to neural cell circuitry are largely uncharted. We now report that ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine-binding (PTB) domain. However, in contrast to the conventional Shc adaptors, ShcD suppresses distal phosphorylation of the Erk MAPK. Accordingly, genetic knock-out of mouse ShcD enhances Erk phosphorylation in the brain. In cultured cells, this capacity is tightly aligned to phosphorylation of ShcD CH1 region tyrosine motifs, which serve as docking platforms for signal transducers, such as Grb2. Erk suppression is relieved through independent mutagenesis of the PTB domain and the CH1 tyrosine residues, and successive substitution of these tyrosines breaks the interaction between ShcD and Grb2, thereby promoting TrkB-Grb2 association. Erk phosphorylation can also be restored in the presence of wild type ShcD through Grb2 overexpression. Conversely, mutation of the ShcD SH2 domain results in enhanced repression of Erk. Although the SH2 domain is a less common binding interface in Shc proteins, we demonstrate that it associates with the Ptpn11 (Shp2) phosphatase, which in turn regulates ShcD tyrosine phosphorylation. We therefore propose a model whereby ShcD competes with neurotrophic receptors for Grb2 binding and opposes activation of the MAPK cascade.
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Melanie K B
authors.initials: MK
authors.lastname: Wills
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Ava
authors.initials: A
authors.lastname: Keyvani Chahi
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Hayley R
authors.initials: HR
authors.lastname: Lau
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Manali
authors.initials: M
authors.lastname: Tilak
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Brianna D
authors.initials: BD
authors.lastname: Guild
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Laura A
authors.initials: LA
authors.lastname: New
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
authors.forename: Peihua
authors.initials: P
authors.lastname: Lu
authors.affiliation: Cancer Research Centre, Quebec Network for Research on Protein Function, Engineering, and Applications (PROTEO) and Centre Hospitalier Universitaire de Québec Research Centre-Université Laval, Québec City, Québec G1R 2J6, Canada, and.
authors.forename: Kévin
authors.initials: K
authors.lastname: Jacquet
authors.affiliation: Department of Biochemistry, Western University, London, Ontario N6A 5B7, Canada.
authors.forename: Susan O
authors.initials: SO
authors.lastname: Meakin
authors.affiliation: Cancer Research Centre, Quebec Network for Research on Protein Function, Engineering, and Applications (PROTEO) and Centre Hospitalier Universitaire de Québec Research Centre-Université Laval, Québec City, Québec G1R 2J6, Canada, and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bisson
authors.affiliation: From the Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada, jonesmcb@uoguelph.ca.
authors.forename: Nina
authors.initials: N
authors.lastname: Jones
mesh_terms: D020816:Amino Acid Motifs; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008562:Membrane Glycoproteins; C000611485:NTRK1 protein, human; C519335:SHC4 protein, human; D055765:Shc Signaling Adaptor Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020917:Receptor, trkA; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D048049:Extracellular Signal-Regulated MAP Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: RaLP; ShcD; Shp2; TRK1-transforming tyrosine kinase protein (Trk-A); TrkB; extracellular signal-regulated kinase (ERK); growth factor receptor-bound protein 2 (GRB2); neurotrophin; phosphotyrosine adaptor; signal transduction