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||91, 84||IFN-gamma||1|
|2||113||IFN-alpha/IFN-beta (with STAT1)||1|
|3||92||IL-6, EGF, G-CSF, Prolactin||1, 12, 13|
|5A, 5B||77, 80||IL-2, IL-3, IL-5, IL-7, IL-15, GM-CSF, Tpo||14-20|
|6||94||IL-3, IL-4, IL-13||20, 21|