title: Integrating receptor signal inputs that influence small Rho GTPase activation dynamics at the immunological synapse.
abstract: The Rho GTPase Cdc42 regulates cytoskeletal changes at the immunological synapse (IS) that are critical to T-cell activation. By imaging fluorescent activity biosensors (Raichu) using fluorescence lifetime imaging microscopy, Cdc42 activation was shown to display kinetics that are conditional on the specific receptor input (through two IS-associated receptors, CD3 and beta1 integrin). CD3-triggered Cdc42 activity is dependent on the cyto-2 (NPIY) motif of the beta1 integrin cytoplasmic domain. Perturbations of the ezrin-radixin-moesin (ERM) function blocked CD3- and beta1-dependent increases in Cdc42 activity. Both IS-associated receptors probably lie on a serial molecular pathway and transduce signals through the ERM-dependent machinery that is responsible for the remodeling and stabilization of the synapse. Cdc42 activity is impaired in beta1 integrin-deficient T cells that form conjugates with antigen-presenting cells but is partially restored in the context of an antigen-specific synapse. This restoration of Cdc42 activity is due, at least in part, to the recruitment and activation of beta2 integrin.
authors.affiliation: Richard Dimbleby Department of Cancer Research, King's College London, Guy's Medical School Campus, London, United Kingdom.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Makrogianneli
authors.forename: Leo M
authors.initials: LM
authors.lastname: Carlin
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Keppler
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Matthews
authors.forename: Enyinnaya
authors.initials: E
authors.lastname: Ofo
authors.forename: Anthony
authors.initials: A
authors.lastname: Coolen
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ameer-Beg
authors.forename: Paul R
authors.initials: PR
authors.lastname: Barber
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017252:CD3 Complex / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000201:enzymology*; D019012:Integrin beta1 / Q000737:chemistry / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D018089:Superantigens / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099149:Ezrin
chemical_list: D017252:CD3 Complex; D003598:Cytoskeletal Proteins; D019012:Integrin beta1; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018089:Superantigens; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000099149:Ezrin; C071058:moesin; C071776:radixin