title: LKB1 regulates TCR-mediated PLCγ1 activation and thymocyte positive selection.
abstract: The serine/threonine kinase LKB1 is a tumour suppressor that regulates cell growth, polarity, and proliferation in many different cell types. We previously demonstrated that LKB1 controls thymocyte survival via regulation of AMPK activation. In this study, we show that LKB1 was also involved in thymocyte positive selection through regulation of T cell receptor (TCR) signalling. Both Lck-Cre- and CD4-Cre-mediated deletion of LKB1 impaired the generation of mature CD4 and CD8 single positive (SP) thymocytes that might have resulted from the attenuated tyrosine phosphorylation of phospholipase C-γ 1 (PLCγ1) in the absence of LKB1. We found that LKB1 was directly phosphorylated by Lck at tyrosine residues 36, 261, and 365 and predominately interacted with LAT and PLCγ1 following TCR stimulation. Loss of LKB1 led to impaired recruitment of PLCγ1 to the LAT signalosome. Correlatively, LKB1-deficient thymocytes failed to upregulate lineage-specifying factors, and to differentiate into SP thymocytes even if their impaired survival was rescued. These observations indicated that LKB1 is a critical component involved in TCR signalling, and our studies provide novel insights into the mechanisms of LKB1-mediated thymocyte development.
authors.affiliation: Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Cao
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.forename: Haifeng
authors.initials: H
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D051966:Phospholipase C gamma / Q000096:biosynthesis*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D051966:Phospholipase C gamma