| First Author | Sommers CL | Year | 2001 |
| Journal | J Exp Med | Volume | 194 |
| Issue | 2 | Pages | 135-42 |
| PubMed ID | 11457888 | Mgi Jnum | J:77695 |
| Mgi Id | MGI:2182399 | Doi | 10.1084/jem.194.2.135 |
| Citation | Sommers CL, et al. (2001) Knock-in mutation of the distal four tyrosines of linker for activation of T cells blocks murine T cell development. J Exp Med 194(2):135-42 |
| abstractText | The integral membrane adapter protein linker for activation of T cells (LAT) performs a critical function in T cell antigen receptor (TCR) signal transduction by coupling the TCR to downstream signaling pathways. After TCR engagement, LAT is tyrosine phosphorylated by ZAP-70 creating docking sites for multiple src homology 2-containing effector proteins. In the Jurkat T cell line, the distal four tyrosines of LAT bind PLCgamma-1, Grb2, and Gads. Mutation of these four tyrosine residues to phenylalanine (4YF) blocked TCR-mediated calcium mobilization, Erk activation, and nuclear factor (NF)-AT activation. In this study, we examined whether these four tyrosine residues were essential for T cell development by generating LAT 'knock-in' mutant mice that express the 4YF mutant protein under the control of endogenous LAT regulatory sequences. Significantly, the phenotype of 4YF knock-in mice was identical to LAT(-/)- (null) mice; thymocyte development was arrested at the immature CD4(-)CD8(-) stage and no mature T cells were present. Knock-in mice expressing wild-type LAT protein, generated by a similar strategy, displayed a normal T cell developmental profile. These results demonstrate that the distal four tyrosine residues of LAT are essential for preTCR signaling and T cell development in vivo. |
