Cytokines and Stat Signaling
Christian Schindler lnga Strehlow
Departments of Microbiology and Medicine College of Physicians and Surgeons Columbia University New York, NY 10032
Cytokines and STAT Signaling
1. Introduction
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
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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
Departments of Microbiology and Medicine College of Physicians and Surgeons Columbia University New York, NY 10032
Cytokines and STAT Signaling
1. Introduction
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
I I3
II4
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