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AIP1: a new player in TNF signaling
M. Eugenia Guicciardi and Gregory J. Gores
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota, USA
Address correspondence to: Gregory J. Gores, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. Phone: (507) 284-0686; Fax: (507) 284-0762; E-mail: gores.gregory@mayo.edu.
Find articles by Guicciardi, M. in: JCI | PubMed | Google Scholar
Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota, USA
Address correspondence to: Gregory J. Gores, Mayo Medical School, Clinic, and Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA. Phone: (507) 284-0686; Fax: (507) 284-0762; E-mail: gores.gregory@mayo.edu.
Find articles by Gores, G. in: JCI | PubMed | Google Scholar
Published June 15, 2003 - More info
J Clin Invest. 2003;111(12):1813–1815. https://doi.org/10.1172/JCI18911.
© 2003 The American Society for Clinical Investigation
The signaling system generated by the binding of TNF to its cognate TNF-receptor (TNF-R) can contain two distinct type I transmembrane receptors, TNF-R1 and TNF-R2, and three ligands, the membrane-bound TNF-α, the soluble TNF-α, and the soluble lymphocyte-derived cytokine lymphotoxin-α (LT-α) (1). Both receptors are ubiquitously expressed in cells and interact with both forms of TNF-α, as well as with LT-α. However, TNF-R1 is the most potent in inducing cytotoxic signals. TNF-R1 is a typical death receptor with a 60- to 80-amino acid cytoplasmic sequence known as the death domain. The death domain, which is missing from TNF-R2, typically enables death receptors to initiate cytotoxic signals. Because of the role of TNF-α in human diseases (2), TNF-R1 signaling mechanisms are of considerable biomedical interest.
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TNF-R1 signaling pathways
The intracellular signals originating from TNF-R1 are extremely complex and can lead to multiple, even opposite, cell responses including cell proliferation, inflammation, or cell death. Survival signals likely prevail over death signals under normal circumstances, given the resistance of most cells to TNF-α–induced toxicity. However, these cells can often be sensitized to TNF-α–mediated apoptosis by blocking protein or RNA synthesis, which suggests that neo-synthesis of protein is required to suppress the apoptotic stimulus. The expression of these antiapoptotic proteins is largely controlled by the activity of the transcription factor NF-κB, as inhibition of NF-κB also sensitizes cells to TNF-α–induced cell death (3).
Binding of TNF-R1 to TNF-α results in conformational changes in the receptor’s intracellular domain, resulting in rapid recruitment of several cytoplasmic death domain–containing adapter proteins via homophilic interaction with the death domain of the receptor (1). The first adaptor recruited to the clustered receptor is the TNF-R–associated protein with death domain, which functions as a docking protein for several signaling molecules, such as Fas-associated protein with death domain (FADD), TNF-R–associated factor-2 (TRAF-2), and receptor-interacting protein (RIP). Recruitment of FADD to the receptor promotes apoptosis by activation of caspase-8 and, possibly, caspase-10 (4). RIP associates with TRAF-2 to generate two distinct pathways (5). The first one signals through the activation of NF-κB–inducing kinase, NIK, and the catalytic IκB kinase complex, leading to phosphorylation of the NF-κB inhibitory protein IκB-α and translocation of NF-κB to the nucleus. The second pathway involves the MAPK cascade, and culminates in the activation of JNK/stress-activated protein kinase and p38 kinase. Both JNK and p38 play an important role in inflammatory responses. JNK has been described to phosphorylate and activate a number of transcription factors, including c-Jun, activating–transcription factor 2 and activator protein-1 (AP-1), which drive the expression of many proinflammatory molecules, including E-selectin, RANTES, IL-12, IL-6, and IL-8 (6). Activation of p38 is essential for production of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, and for induction and expression of inflammatory-related enzymes such as COX-2 and iNOS (7).
MAPKs are activated by a well-recognized mechanism of dual phosphorylation mediated by one of the MAP kinase kinases (MAPKKs), which, in turn, are activated through phosphorylation by MAP kinase kinase kinases (MAPKKKs) (Figure 1a). Previous studies have shown that TNF-α–induced activation of JNK and p38 is mediated by the recruitment of the adaptor TRAF-2 and subsequent activation of the MAPKKK apoptosis signal–regulating kinase 1 (ASK1) (8). ASK1, a 170-kDa Ser/Thr kinase, activates the JNK and p38 MAPK signaling cascades in response to proinflammatory cytokines and oxidative stress. Overexpression of ASK1 in epithelial cells induces apoptosis, whereas a kinase-inactive mutant of ASK1 protects the cells from TNF-induced apoptosis, suggesting that ASK1 is involved in the TNF apoptotic signaling pathway (9). Functionally, ASK1 is composed of an inhibitory NH2-terminal domain, an internal kinase domain, and a COOH-terminal regulatory domain. The COOH-terminal domain of ASK1 binds to the TRAF domain of TRAF-2 and TRAF-6 (8). The kinase domain is required for cytokine-induced JNK activation and cell death (9, 10). The NH2-terminus contains an inhibitory domain that interacts with several cellular proteins and prevents ASK1 activation (11, 12). Although 14-3-3, a family of dimeric phosphoserine-binding molecules, binds to ASK1 specifically via Ser-967 in the COOH-terminal domain of ASK1, and inhibits ASK1-induced apoptosis (13), the precise role of 14-3-3 in regulating TNF-induced ASK1 activation has not been determined.
Figure 1(a) Generic schema for the cytokine/adaptor/MAPK signaling paradigm. Cytokines, such as TNF-α, trigger oligomerization of their enzymatically inactive cognate receptors. The conformational change in the receptor complex following ligand binding facilitates recruitment of adaptor proteins. These adaptor proteins within the receptor complex interact directly or indirectly with upstream kinases (MAPKKK) permitting their activation with subsequent phosphorylation and activation of downstream kinases (MAPKK/MAPK). (b) Model of TNF-α signaling pathway through TRAF2/ASK1 employing the cytokine/adaptor/MAPK paradigm. Triggering of TNF-R1 leads to recruitment of the adaptor TRAF2, and concomitant activation of an unknown phosphatase via a mechanism yet to be identified. TRAF2 mediates the association of ASK1 with the newly identified Ras-GAP AIP1, which facilitates the release of ASK1 from its endogenous inhibitor 14-3-3. Disruption of the ASK1/14-3-3 complex and de-phosphorylation of ASK1 by the unknown phosphatase result in the activation of ASK1. ASK1, in turn, activates JNK via an MKK4- or MKK6-dependent pathway. Activation of JNK positively regulates the apoptotic machinery by transcription-dependent (i.e., activation of the transcription factor AP-1) and transcription-independent (i.e., phosphorylation and activation of proapototic Bcl-2 proteins Bim and Bmf) mechanisms. P, phosphate.
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