title: Nuclear lymphocyte-specific protein tyrosine kinase and its interaction with CR6-interacting factor 1 promote the survival of human leukemic T cells.
abstract: Overexpression and hyperactivation of lymphocyte-specific protein tyrosine kinase (Lck) have been associated with leukemia development. We previously showed that, other than its known function as a cytoplasmic signal transducer, Lck also acts as a nuclear transcription factor in mouse leukemic cells. In the present study, we demonstrated the presence of nuclear Lck in human leukemic T cells and in primary cells. We further established a positive correlation between Lck nuclear localization and its kinase activity. Proteomic analysis identified CR6-interacting factor 1 (CRIF1) as one of the Lck-interacting proteins. CRIF1 and Lck association in the nucleus was confirmed both by immunofluorescence microscopy and co-immunoprecipitation in human leukemic T cells. Close-range interaction between Lck and CRIF1 was validated by in situ proximity ligation assay (PLA). Consistent with the role of nuclear CRIF1 as a tumor suppressor, CRIF1 silencing promotes leukemic T cell survival in the absence of growth factors. This protective effect can be recapitulated by endogenous Lck or reconstituted Lck in leukemic T cells. All together, our results support a novel function of nuclear Lck in promoting human leukemic T cell survival through interaction with a tumor suppressor. It has important implications in defining a paradigm shift of non-canonical protein tyrosine kinase signaling.
authors.affiliation: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Shahrooz
authors.initials: S
authors.lastname: Vahedi
authors.affiliation: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Fu-Yu
authors.initials: FY
authors.lastname: Chueh
authors.affiliation: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Bala
authors.initials: B
authors.lastname: Chandran
authors.affiliation: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Chao-Lan
authors.initials: CL
authors.lastname: Yu
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D060066:Protein Interaction Maps / Q000235:genetics*; D040901:Proteomics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; C476586:GADD45GIP1 protein, human; D009687:Nuclear Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)