The T cell protein tyrosine phosphatase is a negative regulator of janus family kinases 1 and 3.
BACKGROUND
The immune response is regulated through a tightly controlled cytokine network. The counteracting balance between protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) activity regulates intracellular signaling in the immune system initiated by these extracellular polypeptides. Mice deficient for the T cell protein tyrosine phosphatase (TCPTP) display gross defects in the hematopoietic compartment, indicating a critical role for TCPTP in the regulation of immune homeostasis. To date, the molecular basis underlying this phenotype has not been reported.


RESULTS
We have identified two members of the Janus family of tyrosine kinases (JAKs), JAK1 and JAK3, as bona fide substrates of TCPTP. Inherent substrate specificity in the TCPTP-JAK interaction is demonstrated by the inability of other closely related PTP family members to form an in vivo interaction with the JAKs in hematopoietic cells. In keeping with a negative regulatory role for TCPTP in cytokine signaling, expression of TCPTP in T cells abrogated phosphorylation of STAT5 following interleukin (IL)-2 stimulation. TCPTP-deficient lymphocytes treated with IL-2 had increased levels of tyrosine-phosphorylated STAT5, and thymocytes treated with interferon (IFN)-alpha or IFN-gamma had increased tyrosine-phosphorylated STAT1. Hyperphosphorylation of JAK1 and elevated expression of iNOS was observed in IFN-gamma-treated, TCPTP-deficient, bone marrow-derived macrophages.


CONCLUSIONS
We have identified JAK1 and JAK3 as physiological substrates of TCPTP. These results indicate a negative regulatory role for TCPTP in cytokine signaling and provide insight into the molecular defect underlying the phenotype of TCPTP-deficient animals.
Simoncic
Paul D
PD
Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada.
Lee-Loy
Ailsa
A
Barber
Dwayne L
DL
Tremblay
Michel L
ML
McGlade
C Jane
CJ
D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D011233:Precipitin Tests; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D001224:Aspartic Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516653:Ptpn2 protein, mouse