title: Gasp, a Grb2-associating protein, is critical for positive selection of thymocytes.
abstract: T cells develop in the thymus through positive and negative selection, which are responsible for shaping the T cell receptor (TCR) repertoire. To elucidate the molecular mechanisms involved in selection remains an area of intense interest. Here, we identified and characterized a gene product Gasp (Grb2-associating protein, also called Themis) that is critically required for positive selection. Gasp is a cytosolic protein with no known functional motifs that is expressed only in T cells, especially immature CD4/CD8 double positive (DP) thymocytes. In the absence of Gasp, differentiation of both CD4 and CD8 single positive cells in the thymus was severely inhibited, whereas all other TCR-induced events such as beta-selection, negative selection, peripheral activation, and homeostatic proliferation were unaffected. We found that Gasp constitutively associates with Grb2 via its N-terminal Src homology 3 domain, suggesting that Gasp acts as a thymocyte-specific adaptor for Grb2 or regulates Ras signaling in DP thymocytes. Collectively, we have described a gene called Gasp that is critical for positive selection.
authors.affiliation: Department of Pathology and Infectious Diseases, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku, Tokyo 162-8655, Japan.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Patrick
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Oda
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sato
authors.forename: Koji
authors.initials: K
authors.lastname: Eshima
authors.forename: Teruo
authors.initials: T
authors.lastname: Kirikae
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Iemura
authors.forename: Mutsunori
authors.initials: M
authors.lastname: Shirai
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Harumi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011506:Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C544192:themis protein, mouse