First printed in R&D Systems' 1996 Catalog.
Since a single cell responds to different cytokines with different transcriptional regulation, there must be a signal transduction pathway that is specific for each cytokine receptor and which involves different transcription activators. At least part of the mechanism involves STAT proteins. For reviews, see references 1-3.
|A model for STAT-mediated activation of gene transcription by IFN-alpha and IFN-gamma. When ligand binds to the receptor, the receptors form dimers. The dimers bind two Jaks, either Jak1 and Tyk2 for IFN-alpha or Jak1 and Jak2 for IFN-gamma. The receptors and the Jaks become phosphorylated, forming the complex that is the catalyst for phosphorylation of STATs. IFN-alpha receptor complex recognizes STAT1 and STAT2, while the IFN-gamma receptor complex recognizes STAT1. The phosphorylated STATs dimerize through association of phosphotyrosine and SH2 domains. The IFN-alpha-induced STAT heterodimer complexes with a 48 kDa DNA-binding protein to form the active gene regulating factor. The IFN-gamma-induced homodimer is not known to require an additional factor. The active STATs bind to a gamma-activated sequence (GAS) or an interferon-stimulated response element (ISRE) of DNA.
STAT is an acronym for Signal Transducer and Activator of Transcription.1 There currently are six known members of the STAT family with masses from 84-113 kDa. STATs transduce a signal from a cytokine receptor to a transcription regulatory element of DNA. STAT proteins are cytoplasmic proteins that are activated by phosphorylation of a specific tyrosine, Tyr701 of STAT1. Phosphorylated STATs dimerize and move to the nucleus, where they bind to specific DNA elements, activating transcription. Dimerization apparently involves an interaction of P-Tyr701 with a SH2 domain that contans an invariant and essential Arg.4 Since each receptor is specific for a certain STAT or STATs and each activated STAT activates transcription of only certain genes, this mechanism explains, in part, cytokine specificity.
The first level of specificity is the interaction of a ligand-activated receptor with a particular STAT. Activation of cytokine receptors leads to tyrosine phosphorylation of the receptor and of receptor-associated Janus kinases (Jaks).1-3 The phosphorylated tyrosine of the receptor is the site for reversible binding of a STAT, and the sequence around the tyrosine confers specificity for a particular STAT.5-10
The second level of specificity is the interaction of dimers of phosphoSTATs with DNA elements. Except for STAT2, they bind to IFN-gamma-activated sequences (GAS), initially identified as sites of interaction of IFN-gamma-induced factors. These sequences, of which there are 10 or so, in general consist of a palindromic sequence, TT Ni AA, where i is 4, 5, or 6.9,11 Recognition of this squence by a particular STAT depends on the value of i as well as on the specific sequence for Ni.For example, binding of STAT3 is better if N is 4, STAT1 if N is 5, and STAT6 if N is 6.9,11 Whether the binding leads to transcription is, however, more complicated, depending on other aspects of the sequence and on flanking sequences.11
|1 alpha, 1 beta
||IFN-alpha/IFN-beta (with STAT1)
||IL-6, EGF, G-CSF, Prolactin
||1, 12, 13
||IL-2, IL-3, IL-5, IL-7, IL-15, GM-CSF, Tpo
||IL-3, IL-4, IL-13
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