Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation.
STAT5, a member of the signal transducers and activators of transcription (STATs), is important in modulating T cell functions through interleukin-2 (IL-2) receptors. Like other STAT proteins, STAT5 undergoes a rapid activation and inactivation cycle upon cytokine stimulation. Tyrosine phosphorylation and dephosphorylation are critical in regulating STAT5 activity. A number of protein tyrosine kinases have been shown to phosphorylate STAT5; however, the phosphatases responsible for STAT5 dephosphorylation remain unidentified. Using CTLL-20 as a model system, we provide evidence that tyrosine dephosphorylation of STAT5 subsequent to IL-2-induced phosphorylation occurs in the absence of STAT5 nuclear translocation and new protein synthesis. Nevertheless, down-regulation of the upstream Janus kinase activity during the deactivation cycle of IL-2-induced signaling does involve new protein synthesis. These findings point to the constitutive presence of STAT5 tyrosine phosphatase activity in the cytosolic compartment. We further demonstrate that SHP-2, but not SHP-1, directly dephosphorylates STAT5 in an in vitro tyrosine phosphatase assay with purified proteins. Furthermore, tyrosine-phosphorylated STAT5 associates with the substrate-trapping mutant (Cys --> Ser) of SHP-2 but not SHP-1. These results suggest a potential role for cytoplasmic protein-tyrosine phosphatases in directly dephosphorylating STAT proteins and in maintaining a basal steady state level of STAT activity.
Yu
C L
CL
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Massachusetts 02115, USA.
Jin
Y J
YJ
Burakoff
S J
SJ
D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D007376:Interleukin-2 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D016399:Lymphoma, T-Cell; D008894:Milk Proteins; D009154:Mutation; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases