title: The Cbl family and other ubiquitin ligases: destructive forces in control of antigen receptor signaling.
abstract: Regulation of tyrosine kinase-mediated cellular activation through antigen receptors is of great biological and practical significance. The evolutionarily conserved Cbl family ubiquitin ligases have emerged as key negative regulators of activated tyrosine kinase-coupled receptors, and their impaired function switches a normal immune response into autoimmunity. Cbl proteins facilitate the ubiquitinylation of activated tyrosine kinases and other signaling proteins and of the signaling chains of receptors themselves; monoubiquitin tag promotes sorting of activated receptors and associated proteins into internal vesicles of the multivesicular body, facilitating their lysosomal degradation, whereas polyubiquitin tag promotes proteasomal degradation. Notably, increased expression of Cbl proteins and other ubiquitin ligases is a component of anergic signaling program in T cells. Thus, controlled destruction of the signaling apparatus has emerged as a key to fine-tuning antigen receptor signaling. Further studies of this pathway are likely to elucidate the pathogenesis of autoimmune diseases and offer new therapeutic targets.
authors.affiliation: Division of Molecular Oncology, Department of Medicine, Evanston Northwestern Healthcare Research Institute, Feinberg School of Medicine, Northwestern University, IL 60201, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Duan
authors.forename: Alagarsamy Lakku
authors.initials: AL
authors.lastname: Reddi
authors.forename: Amiya
authors.initials: A
authors.lastname: Ghosh
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
mesh_terms: D000818:Animals; D007108:Immune Tolerance; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D011946:Receptors, Antigen / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology
chemical_list: D011518:Proto-Oncogene Proteins; D011946:Receptors, Antigen; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases; C067419:CBL protein, human