PubMed Journals: Curr Biol
Source: PMID: 11909529
⇦ ⇨ Curr Biol. 2002 Mar 19;12(6):446-53.
The T cell protein tyrosine phosphatase
is a negative regulator of janus family
kinases 1 and 3.
Simoncic PD(1), Lee-Loy A, Barber DL, Tremblay
ML, McGlade CJ.
(1) Department of Biochemistry and McGill
Cancer Centre, McGill University, Montreal,
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.
PMID: 11909529 [Indexed for MEDLINE]