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Review
. 1999;7(4-6):217-31.

Activation of the AP-1 transcription factor by inflammatory cytokines of the TNF family

J M Kyriakis  1
Affiliations
Review

Activation of the AP-1 transcription factor by inflammatory cytokines of the TNF family

J M Kyriakis. Gene Expr. 1999.

Abstract

Inflammatory cytokines of the tumor necrosis factor (TNF) family mediate a large variety of cellular and organismal inflammatory responses and are important to the pathogenesis of a number of important disease states including arthritis, septic shock, inflammatory bowel disease, and, possibly, type II diabetes. Many of the responses to these cytokines require de novo gene expression mediated by the activator protein-1 (AP-1) heterodimeric transcription factor. This review will discuss what is known of how cytokines of the TNF family, acting at the cell surface, recruit two mitogen-activated protein kinase (MAPK) subfamilies, the stress-activated protein kinases (SAPKs, also called JNKs) and the p38s, to transduce signals to AP-1.

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Figures

FIG. 1
FIG. 1
Recruitment of signaling adapter molecules to TNFR1 and Fas, two TNFR superfamily receptors. Domains responsible for the various interactions are discussed in the text. Adapter protein binding is dependent upon engagement and oligomerization of receptor proteins.
FIG. 2
FIG. 2
Structure of GCK family kinases. (A) Schematic diagram of three representative group-I GCKs: GCK1, HPK1 and NIK [reviewed in (37)]. Structures of MEKK1 and MLK3, MAP3Ks known to bind these GCKs, are also indicated. (B) Sequence alignment of the Leu-rich and CT motifs of the five known mammalian group-I GCKs. Blue shading illustrates residues shared by all five enzymes. Green shading illustrates residues shared by four of the five enzymes. Gray shading indicates residues shared by the three group-I enzymes known to be activated by TNF: GCK1, GCKR and GLK. Red printing delineates the known TRAF2 binding regions (the CT motifs) of GCK and GCKR. A consensus sequence is shown. Green printing indicates the conserved amino-terminal extension of the Leu-rich domain present in GCK1, GCKR, GLK, and HPK1 and absent in NIK. See text for details. Alignment was achieved using the PILEUP and CLUSTAL-W programs and further optimized by eye.
FIG. 2
FIG. 2
Structure of GCK family kinases. (A) Schematic diagram of three representative group-I GCKs: GCK1, HPK1 and NIK [reviewed in (37)]. Structures of MEKK1 and MLK3, MAP3Ks known to bind these GCKs, are also indicated. (B) Sequence alignment of the Leu-rich and CT motifs of the five known mammalian group-I GCKs. Blue shading illustrates residues shared by all five enzymes. Green shading illustrates residues shared by four of the five enzymes. Gray shading indicates residues shared by the three group-I enzymes known to be activated by TNF: GCK1, GCKR and GLK. Red printing delineates the known TRAF2 binding regions (the CT motifs) of GCK and GCKR. A consensus sequence is shown. Green printing indicates the conserved amino-terminal extension of the Leu-rich domain present in GCK1, GCKR, GLK, and HPK1 and absent in NIK. See text for details. Alignment was achieved using the PILEUP and CLUSTAL-W programs and further optimized by eye.
FIG. 3
FIG. 3
Signaling from TRAF2 to GCK and MEKK1. GCK is activated as a consequence of binding TRAF2; although the mechanism has not been characterized completely, the kinase activity of GCK is likely ultimately enhanced by TRAF2. Activated GCK then binds MEKK1. Results (76) indicate that the kinase activity of GCK permits binding of MEKK1 and efficient turnover of activated MEKK1. The exact mechanism of MEKK1 activation is still largely unclear.
FIG. 4
FIG. 4
Recruitment of elements upstream of the SAPKs and p38s by the TNFR complex. See Fig. 1 and text for details on formation of the TNFR complex. The various domains involved in the molecular interactions shown are illustrated in the key.
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