Departments of Microbiology and Medicine College of Physicians and Surgeons Columbia University New York, NY 10032
Cytokines and STAT Signaling
First discovered as the major signal transducer in interferon-mediated gene activation, STATs (signal transducers and activators of transcription) are now known to play a significant role in signal transduction for most cytokines. STATs represent a family of conserved proteins, seven of which have been identified in mammals (i.e., Statl, 2, 3 , 4 , Say5b, and 6; Darnell, 1997; Ihle et al., 1994; Schindler and Darnell, 1995). Homologues have also been identified in lower eukaryotes (Hou et al., 1996; Kawata et al., 1997; Yan et al., 1996).JAKs are receptor-associated tyrosine kinases, which mediate the ligand dependent activation of STATs. These two protein families are the defining components of the JAK-STAT pathway. The JAK-STAT signaling paradigm (see Fig. 1)has been well characterized for many ligands (reviewed in Darnell, 1997; Ihle et al., 1994; Schindler and Darnell, 1995). Briefly, upon binding ligand a receptor will dimerize. This enables receptor-associated JAKs to become activated, which in turn phosphorylate tyrosine motifs in the cytoplasmic tail of the receptor. These receptor tyrosine motifs are recognized by the SH2 domains of STATs, thereby mediating the recruitment of the appropriate STAT to the receptor complex. Once at the receptor, JAKs phosphorylate STATs on a conserved Hormones and Signaling Copyright Q 2000 by Academic Press. All rights of reproduction in any form reserved. 1054-3589100 $30.00
Schindler & Strehlow
FIGURE I The IFN-.)Istimulated JAK-STAT pathway. When IFN-.)Ibinds its receptor, twoassociated tyrosine kinase, Jakl and Jak2, become activated. These kinases then phosphorylate a receptor tyrosyl residue, which is in turn specifically recognized by the SH2 domain of Statl. Once recruited to the receptor, Statl becomes phosphorylated by the JAKs. Now activated, Statl is released from the receptor and forms homodimers, which are competent for nuclear translocation. Once in the nucleus the Statl homodimer binds a member of the GAS family of enhancers, culminating in transcription. See text for details.
tyrosine. Activated STATs are released from the receptor and dimerize through the interaction of the SH2 domain of one STAT with the phosphotyrosine of the other STAT. These dimers translocate to the nucleus, where they bind to members of the GAS (IFN-gamma activation site) family of enhancers, culminating in the transcription of genes. STATs thus transduce high-fidelity signals directly from the cell surface to target genes. The past 2 years have seen significant progress in the characterization of the JAK-STAT signaling cascade. Important developments have included the establishment of murine “knockout” models and the resolution of the crystal structure of two STATs. Another exciting area of progress has been in the identification of molecules that modify signaling through the STAT pathway. These more recent developments will be the focus of this review.
II. STAT Domains
STATs share a number of functionally conserved domains (see Fig. 2), including an amino terminal domain (NH,), a coiled-coil domain, a DNA binding domain (DBD), an SH2 domain, and a tyrosine activation domain (Y). The transcriptional activation domain (TAD) is carboxy terminal and
Cytokines and STAT Signaling
STAT structure. STATs share a number of conserved domains, including an amino terminal domain (NHr),a coiled-coil domain, a D N A binding domain (DBD), a linker domain, an SH2 domain, and a tyrosine activation domain ( Y ) . The sequences carboxy terminal to this tyrosine activation domain are not conserved, but they do encode a transcriptional activation domain (TAD). See text for details.