title: Genetic analysis of SH2D4A, a novel adapter protein related to T cell-specific adapter and adapter protein in lymphocytes of unknown function, reveals a redundant function in T cells.
abstract: T cell-specific adapter (TSAd) protein and adapter protein in lymphocytes of unknown function (ALX) are two related Src homology 2 (SH2) domain-containing signaling adapter molecules that have both been shown to regulate TCR signal transduction in T cells. TSAd is required for normal TCR-induced synthesis of IL-2 and other cytokines in T cells and acts at least in part by promoting activation of the LCK protein tyrosine kinase at the outset of the TCR signaling cascade. By contrast, ALX functions as a negative-regulator of TCR-induced IL-2 synthesis through as yet undetermined mechanisms. In this study, we report a novel T cell-expressed adapter protein named SH2D4A that contains an SH2 domain that is highly homologous to the TSAd protein and ALX SH2 domains and that shares other structural features with these adapters. To examine the function of SH2D4A in T cells we produced SH2D4A-deficient mice by homologous recombination in embryonic stem cells. T cell development, homeostasis, proliferation, and function were all found to be normal in these mice. Furthermore, knockdown of SH2D4A expression in human T cells did not impact upon their function. We conclude that in contrast to TSAd and ALX proteins, SH2D4A is dispensable for TCR signal transduction in T cells.
authors.affiliation: Department of Microbiology and Immunology, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Lapinski
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Oliver
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Kamen
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Hughes
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000235:genetics; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C474507:SH2D4A protein, human; C521227:sh2d4a protein, mouse