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

esponse once a second signal for tyrosine phosphorylation is received (Decker and Kovarik,
2000). Furthermore, serine phosphorylation may augment transcriptional responsiveness
through altered co-factor recruitment, for example, serine phosphorylation of STAT3 has
been shown to influence recruitment of the co-factor p300/CBP, a histone acetyl transferase
(HAT) which facilitates chromatin unwinding and transcription factor access to target DNA
(Schuringa et al., 2001). Evidence for the important role for STAT serine phosphorylation in
vivo comes from studies of mutant mice where the serine residue at position 727 is mutated to
an alanine (S727A). STAT1 S727A mice displayed increased mortality upon Listeria
monocytogenes infection and have increased resistance to LPS-induced endotoxic shock,
however this mutation only affects a subset of STAT1 target genes (Varinou et al., 2003). In
contrast, STAT3 S727A mice exhibited 75% perinatal lethality and are more sensitive to
LPS-induced endotoxic shock (Shen et al., 2004, Shen et al, 2005).
By having two modes of activation, tyrosine and serine phosphorylation allow tight
regulation of STAT activity so that signals from several pathways can converge to modulate
STAT induced gene activation. Recently Kovarik’s group demonstrated that STAT1 Y701
phosphorylation and nuclear translocation were a prerequisite for serine phosphorylation by
interferons (Sadzak et al., 2008). Moreover, STAT1 mutants which were unable to associate
with chromatin were refractory for S727 phosphorylation, suggesting that STAT1 needs to be
assembled into chromatin-associated transcriptional complexes to become S727-
phosphorylated and fully biologically active in response to IFNs.
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