Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

IFN- and EGF and repress both tyrosine and serine phosphorylation in the nucleus (Wu et
al., 2002). This association is exploited by the human cytomegalovirus which increases SHP2
binding to STAT1, reducing STAT1 phosphorylation and thereby dampening the antiviral
response (Davon and Barignon, 2008).
Less is known about phosphatases which target STAT3, but recently a tyrosine
phosphopeptide screen of cells overexpressing the receptor protein tyrosine phosphatase T
(PTPRT) identified STAT3 as a substrate (Zhang et al., 2007). RNAi mediated inhibition of
PTPRT in MCF-7 cells significantly increased STAT3 Y705 phosphorylation and
overexpression of PTPRT dramatically reduced IL-6 mediated STAT3 tyrosine
phosphorylation and nuclear translocation as well as reducing STAT3 target gene expression.
T cell protein tyrosine phosphatase TC-PTP has also shown to be capable of
dephosphorylating STAT3 following IL-6 treatment in 293 cells (Yammamoto et al., 2002).
These studies show that in addition to the regulatory mechanisms involved in STAT
activation there are signaling pathways which limit the duration of STAT phosphorylation.
This is necessary to avoid any unwanted side effects of prolonged STAT activation. For
example, dysregulated phosphorylation of STAT1 might lead to an excessive inflammatory
response or increased levels of apoptosis. It is also necessary in allowing repeated rounds of
STAT activation; STAT dephosphorylation allows STATs to be returned to the cytosol where
they can once again be phosphorylated. In the future, more detailed understanding of STAT
dephosphorylation will add to our knowledge of the regulation of the JAK/STAT pathway.
1.3.7 Negative Regulation of STATs by SOCS
The suppressor of cytokine signaling (SOCS) proteins control the negative regulation of
cytokine responses. There are seven members of the SOCS family (SOCS1-7) which are all
induced by cytokines and therefore they form part of a negative feedback loop of cytokine
control, in addition SOCS proteins can be induced by other agonists such as LPS, statins and
cAMP. SOCS1 and SOCS3 are potent inhibitors of the JAK/STAT pathway, The SH2
domain of SOCS1 and SOCS3 is necessary to facilitate binding to a site in active JAK1,
JAK2 and Tyk2 while the SOCS kinase inhibitory region (KIR) is responsible for
suppressing JAK kinase activity (Narazaki et al., 1998, Sasaki et al., 1999). The SOCS SH2
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