A Dominant-negative Transgene Defines a Role for P56lck in Thymopoiesis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1993 Apr 1

PMID 8385609

Citations 60

Authors

S D Levin

S J Anderson

K A Forbush

R M Perlmutter

Affiliations

Soon will be listed here.

Abstract

The lymphocyte-specific protein tyrosine kinase p56lck participates in T cell signaling through functional interactions with components of the T cell antigen receptor complex and the interleukin-2 receptor. Additional insight into the function of p56lck has now been obtained through the generation of transgenic animals expressing high levels of a catalytically inactive form of this kinase (p56lckR273). Mice bearing the lckR273 transgene manifested a severe defect in the production of virtually all T lymphocytes. Those exceptional CD3+ cells that escaped the effects of the lckR273 transgene were confined primarily to the T cell subset that expresses gamma/delta T cell receptors. Remarkably, construction of a dose-response curve for the effects of the lckR273 transgene revealed that developmental arrest of thymocytes occurred at a discrete stage in the normal T cell maturation pathway, corresponding to a point at which thymoblasts ordinarily begin a series of mitotic divisions that result in expansion and maturation. These results suggest that p56lck normally regulates T cell production by metering the replicative potential of immature thymoblasts.

Citing Articles

Type of PaperY192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection.

Kastle M, Merten C, Hartig R, Plaza-Sirvent C, Schmitz I, Bommhardt U Int J Mol Sci. 2022; 23(13).

PMID: 35806279 PMC: 9267008. DOI: 10.3390/ijms23137271.

Identification of Potential Biomarkers of Type 2 Diabetes Mellitus-Related Immune Infiltration Using Weighted Gene Coexpression Network Analysis.

Zhou J, Zhang X, Ji L, Jiang G Biomed Res Int. 2022; 2022:9920744.

PMID: 35187175 PMC: 8849810. DOI: 10.1155/2022/9920744.

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified.

Debackere K, Marcelis L, Demeyer S, Vanden Bempt M, Mentens N, Gielen O Nat Commun. 2021; 12(1):3705.

PMID: 34140493 PMC: 8211700. DOI: 10.1038/s41467-021-24037-4.

Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation.

Patsoukis N, Duke-Cohan J, Chaudhri A, Aksoylar H, Wang Q, Council A Commun Biol. 2020; 3(1):128.

PMID: 32184441 PMC: 7078208. DOI: 10.1038/s42003-020-0845-0.

Evaluation of Serum Zinc Level Under Malignant Condition and its Possible Implication on Improving Cell-Mediated Immunity During Cancer Progression.

Chakravarty P World J Oncol. 2017; 2(1):16-23.

PMID: 29147221 PMC: 5649884. DOI: 10.4021/wjon256e.

References

Schlissel M, Baltimore D . Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell. 1989; 58(5):1001-7. DOI: 10.1016/0092-8674(89)90951-3. View

Hemsley A, Arnheim N, Toney M, Cortopassi G, Galas D . A simple method for site-directed mutagenesis using the polymerase chain reaction. Nucleic Acids Res. 1989; 17(16):6545-51. PMC: 318348. DOI: 10.1093/nar/17.16.6545. View

Egerton M, Shortman K, Scollay R . The kinetics of immature murine thymocyte development in vivo. Int Immunol. 1990; 2(6):501-7. DOI: 10.1093/intimm/2.6.501. View

Chalupny N, Ledbetter J, Kavathas P . Association of CD8 with p56lck is required for early T cell signalling events. EMBO J. 1991; 10(5):1201-7. PMC: 452774. DOI: 10.1002/j.1460-2075.1991.tb08061.x. View

Abraham K, Levin S, Marth J, Forbush K, Perlmutter R . Thymic tumorigenesis induced by overexpression of p56lck. Proc Natl Acad Sci U S A. 1991; 88(9):3977-81. PMC: 51576. DOI: 10.1073/pnas.88.9.3977. View

Abraham K, Levin S, Marth J, Forbush K, Perlmutter R . Delayed thymocyte development induced by augmented expression of p56lck. J Exp Med. 1991; 173(6):1421-32. PMC: 2190838. DOI: 10.1084/jem.173.6.1421. View

Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin S, Perlmutter R . Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science. 1991; 252(5012):1523-8. DOI: 10.1126/science.2047859. View

Raulet D, Spencer D, Hsiang Y, Goldman J, Bix M, Liao N . Control of gamma delta T-cell development. Immunol Rev. 1991; 120:185-204. DOI: 10.1111/j.1600-065x.1991.tb00592.x. View

Bolen J, Thompson P, Eiseman E, Horak I . Expression and interactions of the Src family of tyrosine protein kinases in T lymphocytes. Adv Cancer Res. 1991; 57:103-49. DOI: 10.1016/s0065-230x(08)60997-5. View

10.

Perlmutter R . Translational regulation of the lymphocyte-specific protein tyrosine kinase p56lck. Enzyme. 1990; 44(1-4):214-24. DOI: 10.1159/000468759. View

11.

Cooke M, Abraham K, Forbush K, Perlmutter R . Regulation of T cell receptor signaling by a src family protein-tyrosine kinase (p59fyn). Cell. 1991; 65(2):281-91. DOI: 10.1016/0092-8674(91)90162-r. View

12.

van Oers N, Garvin A, Davis C, Forbush K, Carlow D, Littman D . Disruption of CD8-dependent negative and positive selection of thymocytes is correlated with a decreased association between CD8 and the protein tyrosine kinase, p56lck. Eur J Immunol. 1992; 22(3):735-43. DOI: 10.1002/eji.1830220317. View

13.

Zamoyska R, Derham P, Gorman S, Von Hoegen P, Bolen J, Veillette A . Inability of CD8 alpha' polypeptides to associate with p56lck correlates with impaired function in vitro and lack of expression in vivo. Nature. 1989; 342(6247):278-81. DOI: 10.1038/342278a0. View

14.

Tan J, Nocka K, Ray P, Traktman P, Besmer P . The dominant W42 spotting phenotype results from a missense mutation in the c-kit receptor kinase. Science. 1990; 247(4939):209-12. DOI: 10.1126/science.1688471. View

15.

Ferrier P, Krippl B, Blackwell T, Furley A, Suh H, Winoto A . Separate elements control DJ and VDJ rearrangement in a transgenic recombination substrate. EMBO J. 1990; 9(1):117-25. PMC: 551637. DOI: 10.1002/j.1460-2075.1990.tb08087.x. View

16.

Dent A, Matis L, Hooshmand F, Widacki S, Bluestone J, Hedrick S . Self-reactive gamma delta T cells are eliminated in the thymus. Nature. 1990; 343(6260):714-9. DOI: 10.1038/343714a0. View

17.

Letourneur F, Gabert J, Cosson P, Blanc D, Davoust J, Malissen B . A signaling role for the cytoplasmic segment of the CD8 alpha chain detected under limiting stimulatory conditions. Proc Natl Acad Sci U S A. 1990; 87(6):2339-43. PMC: 53682. DOI: 10.1073/pnas.87.6.2339. View

18.

van Meerwijk J, Bluthmann H, Steinmetz M . T-cell specific rearrangement of T-cell receptor beta transgenes in mice. EMBO J. 1990; 9(4):1057-62. PMC: 551779. DOI: 10.1002/j.1460-2075.1990.tb08210.x. View

19.

Nocka K, Tan J, Chiu E, Chu T, Ray P, Traktman P . Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. EMBO J. 1990; 9(6):1805-13. PMC: 551885. DOI: 10.1002/j.1460-2075.1990.tb08305.x. View

20.

Baron C, Penit C . Study of the thymocyte cell cycle by bivariate analysis of incorporated bromodeoxyuridine and DNA content. Eur J Immunol. 1990; 20(6):1231-6. DOI: 10.1002/eji.1830200606. View