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 N_i 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 N_i.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

References

1. Darnell, J.E. et al. (1994) Science 264:1415.
2. Ihle, J.N. et al. Trends Biochem. Sci. 19:222.
3. Ihle, J.N. and I.M. Kerr (1995) Trends Genetics 11:69.
4. Shuai, K. et al. (1993) Nature (London) 366:580.
5. Greenlund, A.C. et al. (1994) EMBO J. 13:1591.
6. Heim, H.H. et al. (1995) Science 267:1347.
7. Stahl, N. et al. (1995) Science 267:1349.
8. Shuai, K. et al. (1994) Cell 76:821.
9. Schindler, U. et al. (1995) Immunity 2:689.
10. Greenlund, A.C. et al. (1995) Immunity 2:677.
11. Seidel, H.M. et al. (1995) Proc. Natl. Acad. Sci. USA 92:3041.
12. Zhong, Z. et al. (1994) Proc. Natl. Acad. Sci. USA 91:4806.
13. Zhong, Z. et al. (1994) Science 264:95.
14. Wakao, H. et al. (1995) EMBO J. 14:2527.
15. Pallard, C. (1995) J. Biol. Chem. 270:15942.
16. Pallard, C. (1995) EMBO J. 14:2847.
17. Gouilleux, F. (1995) EMBO J. 14:2005.
18. Mui, A.L. et al. (1995) J. Leukoc. Biol. 57:799.
19. Azam, M. et al. (1995) EMBO J. 14:1402.
20. Lin, J.X. et al. (1995) Immunity 2:331.
21. Quelle, F.W. (1995) Mol. Cell. Biol. 15:3336.