title: Lck domains differentially contribute to pre-T cell receptor (TCR)- and TCR-alpha/beta-regulated developmental transitions.
abstract: Maturational changes at the CD4(-)CD8(-) double negative (DN) to CD4(+)CD8(+) double positive (DP) transition are dependent on signals generated via the pre-T cell receptor (TCR) and the nonreceptor protein tyrosine kinase p56(lck) (Lck). How Lck activities are stimulated or relayed after pre-TCR formation remains obscure. Our structure-function mapping of Lck thymopoietic properties reveals that the noncatalytic domains of Lck are specialized to signal efficient cellular expansion at DN to DP transition. Moreover, although substitution of the Lck catalytic domain with FynT sequences minimally impacts DP development, single positive thymocytes are most efficiently produced in the presence of kinases containing both the NH(2)-terminal and catalytic regions of Lck. These findings demonstrate that the Lck structure is uniquely adapted to mediate signals at both major transitions in thymopoiesis.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lin
authors.forename: N S
authors.initials: NS
authors.lastname: Longo
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: J A
authors.initials: JA
authors.lastname: Hewitt
authors.forename: K M
authors.initials: KM
authors.lastname: Abraham
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D020134:Catalytic Domain; D002454:Cell Differentiation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014162:Transfection
chemical_list: D011518:Proto-Oncogene Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn