HematopoietinInterferon Signaling

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     Schindler et al pdf
                 Janus Kinase Family

    JH7    JH6      JH5       JH4      JH3       JH2/yK          JH1/TK
0    100   200    300   400   500    600   700     800   900   1000   1100   1200

                                    Jak1         Expressed in all tissues

                                                  Expressed in hemato-
                                    Jak3          poietic tissues
STATs & Four Helix Bundle Cytokines

 Stat1        IFN-I(,,,) & IFN-

 Stat2           IFN-I(,,,)

 Stat3        IL-10 and IL-6 families

 Stat4          IL-12, IL-23, IL-27
 Stat5a/b   Single Chain, IL-2 & IL-3 families

 Stat6              IL-4, IL-13
TAD: Transactivation domain; DBD – DNA binding domain
Cyt receptor will have at least two JAKs interacting – JAKS
will ultimately activate STATs to form either a homo or hetero
•   Transduces critical signals for all three classes of IFNs.
•   Stat1 is activated by several other ligands, but its role appears to be more
•   Generic biological activities include:
     – Promoting the expression of inflammatory or “danger” signals.
     – Antagonizing proliferation and/or promoting apoptosis.
     – Stat3 appears to antagonize both of these activities.
•   Stat1 is tyrosine phosphorylated on Y701 and serine phosphorylated on S727 (in
    the TAD). This latter phosphorylation is required for maximal transcription of
    some genes.
•   Stat1 activity is antagonized by phosphatases directed at the receptor and
    JAKs, and directly by one or more nuclear phosphatases.
 • Transduces critical signals for type I IFNs and -IFNs.
 • Murine and Human Stat2 are functionally analogous but
   uncharacteristically divergent in sequence, especially in the TAD.
 • Stat2 is the only STAT that does not appear to homodimerize and bind
   DNA directly.
 • Stat2 activity is antagonized by phosphatases directed at the receptor
   and JAKs, and directly by one or more nuclear phosphatases.
 • STAT1/STAT2/IRF9 bind the interferon stimulated response element
Murine           Coil-Coil         DNA        SH2    Y689         TAD
923 aa
                             76 % Homology                  Divergent

Human            Coil-Coil         DNA        SH2    Y690   TAD
851 aa
•   Transduces signals for type I IFNs,-IFNs, the critical signals for the extended
    IL-10 family and the extended IL-6 families.
•   Generic biological activities include:
     – Promoting cell growth associated with cell transformation.
     – Antagonizing the expression of inflammatory or “danger” signals.
     – Stat1 antagonizes both of these activities (a ying-yang relationship).
•   Stat3 is the only STAT that is essential for development (i.e., the knockout is
    embryonic lethal). Tissues specific knockouts reveal an important roles in
    protecting tissues form inflammation and suppressing transformation.
•   Stat3 is tyrosine phosphorylated at Y705, serine phosphorylated at S727 and
    acetylated at K785.
•   Stat3 activity is antagonized by phosphatases directed at the receptor and
    JAKs, and directly by one or more nuclear phosphatases.
•   Stat3 is important in Th17 development.
                      Stat5a and Stat5b
• Transduce critical signals for all members of the IL-2, IL-3 and single
  chain cytokine receptor families, i.e. is Stat5 is functionally pleiotropic
  like its ancestral partner Stat3.
• Consistent with their significant level of homology, Stat5a & Stat5b can
  functionally overlap, especially in hematopoietic tissues (e.g., in
  response to IL-2 and IL-3 family ligands).
• However, gene targeting studies have underscored a specificity for
  Stat5a in prolactin response and a specificity for Stat5b in GH
• Stat5 has been implicated in the development of some hematopoietic
  tumors and the regulation of some stem cell populations.
                          Stat4 & Stat6

• Stat4 and Stat6 exhibit a the most ligand specificity.
    – Stat4 transduces signals for members of the IL-12 family. (IFN-Is can also
      promote a partial activation of Stat4).
    – Stat6 transduces signals for closely related IL-4 and IL-13.
• Stat4, Stat6 and their activating ligands play an essential role in the
  development of effector CD4+ T-helper cells.
    – Stat4 directs the development of Th1 cells – and is involved in expansion
      of Th17 – through IL-23.
    – Stat6 directs the development of Th2 cells.
• Full Stat4 activation requires both tyrosine phosphorylation at Y689 and
  serine phosphorylation at S721.
Specificity of STATs
Determined by inter-
vening sequence.

STATs usually involved
in activation of gene
transcription –
In many cases, resp.
cytokine also induces
growth signal –
this usually involves
other pathways – ex
is IRS pathway used
by IL-4
  Regulation of JAK-STAT
 Suppressor of cytokine signaling (SOCS)
   Cytokine –inducible SH2 containing
                protein (CIS)
Protein inhibitors of activated STAT (PIAS)
       Protein phosphatases (PTK)
                  SOCS specificity
• Suppressor of Cytokine Signaling 1 (SOCS-1), a Stat1 target gene,
  directs an important negative feed back loop to suppress IFN-Stat1
  dependent signals.
• SOCS-2 specifically antagonizes Stat5b activation in response to
  GH (i.e., SOCS-2 knockout mice exhibit gigantism).
• In response to stimulation by the IL-6 family of ligands, Stat3 activity
  is directly suppressed by SOCS-3, a Stat3 target gene.
Nature Immunology 4, 1169 - 1176 (2003)
Nature Immunology 4, 1169 - 1176 (2003)
         CIS/SOCS Facts
• CIS binds to cytokine receptors—probably
  competes for STAT binding sites
• SOCS proteins bind to JAK kinases – best
  understood is SOCS1 – which binds and
  inhibits all of the JAKS
• SOCS1 KOs die within three weeks of
  birth due to overexpression/overactivity of
  especially IFN

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