Janus kinase 2 is associated with a box 1-like motif and phosphorylates a critical tyrosine residue in the cytoplasmic region of cytotoxic T lymphocyte associated molecule-4.
It is a consensus that a cytotoxic T lymphocyte associated molecule-4 (CTLA-4) transduces inhibitory signal for T cell activation under physiological condition, indicating that this molecule is an important regulator of T cell homeostasis in vivo. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules. The objective of this study is to identify a tyrosine kinase that can directly bind and phosphorylate the critical tyrosine residue, Y-165 in the cytoplasmic domain of CTLA-4. Here, we demonstrated that 1) Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule, 2) Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4 molecule, and 3) Jak2 was associated with CTLA-4 in HUT 78 T cell lines.
Chikuma
S
S
Section of Immunopathogenesis, Institute of Immunological Science, Hokkaido University, Sapporo, 060-0815, Japan.
Murakami
M
M
Tanaka
K
K
Uede
T
T
D000069594:Abatacept; D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D060908:CTLA-4 Antigen; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D018796:Immunoconjugates; D053614:Janus Kinase 2; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010449:Peptide Mapping; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D017931:DNA Primers; D018796:Immunoconjugates; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D000069594:Abatacept; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2