title: NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins.
abstract: T cell receptor (TCR) and costimulatory receptor (CD28) signals cooperate in activating T cells, although understanding of how these pathways are themselves regulated is incomplete. We found that Homer2 and Homer3, members of the Homer family of cytoplasmic scaffolding proteins, are negative regulators of T cell activation. This is achieved through binding of nuclear factor of activated T cells (NFAT) and by competing with calcineurin. Homer-NFAT binding was also antagonized by active serine-threonine kinase AKT, thereby enhancing TCR signaling via calcineurin-dependent dephosphorylation of NFAT. This corresponded with changes in cytokine expression and an increase in effector-memory T cell populations in Homer-deficient mice, which also developed autoimmune-like pathology. These results demonstrate a further means by which costimulatory signals are regulated to control self-reactivity.
authors.affiliation: Program in Biochemistry, Cellular and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Guo N
authors.initials: GN
authors.lastname: Huang
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.forename: Samuel
authors.initials: S
authors.lastname: Bouyain
authors.forename: Jianchen
authors.initials: J
authors.lastname: Tu
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McCorkell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: May
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Zhu
authors.forename: Michael
authors.initials: M
authors.lastname: Lutz
authors.forename: Samuel
authors.initials: S
authors.lastname: Collins
authors.forename: Marlin
authors.initials: M
authors.lastname: Dehoff
authors.forename: Shin
authors.initials: S
authors.lastname: Kang
authors.forename: Katharine
authors.initials: K
authors.lastname: Whartenby
authors.forename: Jonathan
authors.initials: J
authors.lastname: Powell
authors.forename: Daniel
authors.initials: D
authors.lastname: Leahy
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D000072233:Homer Scaffolding Proteins; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D002352:Carrier Proteins; C000606616:HOMER3 protein, human; D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; C000606627:Homer3 protein, mouse; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C494007:Nfatc2 protein, mouse; D011993:Recombinant Fusion Proteins; D051057:Proto-Oncogene Proteins c-akt; D019703:Calcineurin; D002118:Calcium