Review ArticleRegulation of JNK and p38 MAPK in the immune system: Signal integration, propagation and termination
Introduction
The primary function of the immune system is to protect the organism from invading pathogens. To perform this function, the mammalian immune system has developed two components: innate immunity and adaptive immunity. Both arms of immunity recognize invading pathogens as non-self, although they utilize different receptor systems. In adaptive immunity, T and B lymphocytes recognize non-self through antigen-specific receptors, such as T cell receptors (TCRs) and immunoglobulins. These receptors are generated by gene rearrangement, which allows the recognition of a vast number of different antigens. In contrast, innate immune cells, including macrophages and dendritic cells (DCs), utilize an evolutionarily conserved receptor system of pattern recognition. Such pattern-recognition receptors (PRRs), which include Toll-like receptors (TLRs), NOD-like receptors (NLRs) proteins and RIG-I like receptors (RLRs), are germline encoded and do not undergo gene rearrangement [1]. In addition to the antigen receptors and PRRs that are essential to prime adaptive and innate immunity, immune cells also receive a plethora of signals delivered through other receptor systems. For example, for a productive adaptive response to occur, T cells need to be activated by TCRs, co-stimulatory signals and immunoregulatory cytokines such as IL-12 and IL-4, which are known as signals 1, 2, and 3, respectively [2]. Likewise, innate immunity is under the control of cytokine receptors, ITAM-coupled receptors and tyrosine kinase receptors that together with PRRs, dictate the ultimate cellular responses to infectious agents [3], [4], [5].
While pathogen recognition begins at the receptor level, it is the signaling components downstream of each receptor and the way they interact with each other that ultimately determine the specific transcriptional response and immunological outcome. Among the central pathways activated in immune cells are the MAP kinases (MAPKs), a family of serine/threonine kinases. The four well characterized subfamilies of MAPKs include: the extracellular signal-regulated kinases (ERK1/2), c-Jun NH2-terminal kinases (JNK-1/2/3), p38 (p38α/β/γ/δ) and ERK5. Among them, JNK and p38 can be activated by cellular stresses and are collectively known as stress-activated MAPKs. MAPKs contain the signature sequence –TXY–, where T and Y are threonine and tyrosine, and X is glutamate, proline or glycine, in ERK, JNK or p38, respectively [6]. Phosphorylation of both the threonine and tyrosine within this signature sequence is required for MAPK activation. Phosphorylation of MAPKs is achieved via a signaling cascade involving a MAPK kinase (MAPKK or MAP2K) that is responsible for phosphorylation of the appropriate MAPK, and a MAPK kinase (MAPKKK or MAP3K) that phosphorylates and activates MAPKK (Fig. 1) [6]. There are a total of approximately 20 MAP3Ks in mammalian cells, with each of them receiving and integrating specific upstream signals [7], [8]. The main MAP2Ks mediating JNK activation are MKK4 and MKK7, whereas p38 can be activated by MKK3 and MKK6, as well as MAP2K-independent pathways such as TAB1 and ZAP70 [9]. Upon activation, MAPKs regulate key cellular events in the cytoplasm by phosphorylation of membrane-associated and cytoplasmic proteins including other kinases and cytoskeletal elements. Activated MAPKs also translocate to the nucleus to phosphorylate transcription factors such as c-Jun, c-Fos, Elk-1 and c-Myc, which coordinate the expression of downstream target genes [6].
Negative regulation of MAPK activities is effected primarily by MAPK phosphatases (MKPs), also known as dual-specificity phosphatases (DUSPs), a group of approximately 10 phosphatases that dephosphorylate the MAPKs on both the threonine and tyrosine residues in the signature sequence –TXY– [10], [11], [12]. These MKPs have unique and overlapping substrate specificity toward MAPKs, and localize to either cytoplasm or nucleus or both. Some of the MKPs are ubiquitously expressed whereas others are more restricted. Despite the high level of redundancy, recent work has revealed that the immunoregulatory functions of MKPs are rather unique [10], [11], [12].
One of the earliest work highlighting a role of the stress-activated MAPK pathways in immune responses was a report by Su et al. that described JNK-mediated integration of TCR and co-stimulation signals [13]. This was followed by a number of studies that employed mouse genetic approaches to address the immunoregulatory functions of MAPK signaling by deleting various molecules at the MAPK and MAP2K levels, including JNK1, JNK2, MKK3, MKK4, MKK6, MKK7, and individual members of the p38 family. These studies have led to important insight into the molecular mechanisms of immune regulation, and readers are encouraged to read excellent reviews on how MAPKs contribute to the function of the immune system [6], [14], [15].
Despite these studies, however, key questions remained: How do immune cells recognize a plethora of stimuli to properly activate the MAPK modules? Once activated, how is MAPK signaling propagated to effect gene regulation and immune reaction, and how is MAPK activation terminated to avoid exuberant immune responses? Recent studies have provided important answers to these questions, and our review will focus on the stimuli and mechanisms that regulate MAPKs in immune cells. First, we will discuss how MAP3Ks integrate upstream signals from multiple receptors in the innate and adaptive immune systems. Second, we will discuss how downstream signaling molecules bridge MAPK activation to immune responses. Third, we will discuss the function and regulation of MKPs in the feedback modulation of MAPK activities. Given the promises of the drug inhibitors targeting the MAPK pathway in inflammatory diseases, understanding the signaling mechanisms in MAPK regulation is not only insightful from a scientific point of view but also has the potential to be translated into new therapeutic strategies. However, for mechanistic studies, pharmacological inhibitors are well known to cause non-specific or non-physiological effects [16], [17]. Therefore, we will mainly discuss the conclusions obtained from mouse genetic systems, with a focus on studies published during the last five years.
Section snippets
MAP3Ks integrate various upstream signals to induce MAPK activation
A total of 21 kinases have been shown to function as MAP3K, generally having the capacity to activate the MAP kinase pathways after overexpression in cell lines [7], [8]. Notably, overexpression of MAP3Ks can sometimes result in their artificial activation and provoke physiologically irrelevant interactions. The presence of a large number of MAP3Ks suggests that multiple MAP3Ks may be required for any stimulus. Indeed, analyses of MAP3K-deficient mouse embryonic fibroblasts (MEFs) showed that
Propagation of MAPK signaling by downstream pathways
MAPKs mediate inflammatory responses mainly by activating gene expression. A group of sequence-specific transcription factors known as AP-1 are conventional substrates for JNK and p38. For example, c-Jun and ATF2 are well characterized substrates for JNK and p38, respectively. In addition, JNK and p38 can phosphorylate a plethora of intracellular proteins, including transcriptional coregulators, cytoskeletal proteins, translational machine components, and other signaling proteins, which in turn
Negative regulation of MAPKs by MKPs
The magnitude and duration of JNK and p38 signal transduction are critical determinants of its biological effects. Activation of MAPKs occurs within minutes in response to most stimuli and is transient. This suggests that MAPKs function as a biological switch that must be downregulated, both under basal conditions and during adaptation. Inhibition of MAPK activity is effected primarily by MAPK phosphatases (MKPs), a group of approximately 10 dual-specificity phosphatases that dephosphorylate
Concluding remarks
One of the central functions of the stress-activated MAPKs is to orchestrate the immune response. Pharmacological inhibition of the p38 and JNK pathways has proven effective in treating or alleviating various inflammatory conditions [108], [109], [110]. However, the toxicity and undesired adverse effects of such inhibitors are recognized as well, which may arise from perturbed cross-regulatory signaling or self-limiting mechanisms that rely on JNK and p38 activities [111]. In this review, we
Acknowledgments
The authors acknowledge the entire Chi laboratory for stimulating discussions, and Betsy Williford for help with art work for the figures. This work was supported by US National Institutes of Health R01 NS064599 and Cancer Center Support Grant CA021765, National Multiple Sclerosis Grant RG4180-A-1, The Hartwell Foundation Individual Biomedical Research Award, Cancer Research Institute Investigator Award, and the American Lebanese Syrian Associated Charities (to H.C.).
References (111)
- et al.
Pathogen recognition and innate immunity
Cell
(2006) When signaling pathways collide: positive and negative regulation of toll-like receptor signal transduction
Immunity
(2008)- et al.
MAP kinase kinase kinases and innate immunity
Trends Immunol.
(2006) - et al.
JNK is involved in signal integration during costimulation of T lymphocytes
Cell
(1994) - et al.
Regulation of Drosophila p38 activation by specific MAP2 kinase and MAP3 kinase in response to different stimuli
Cell Signal
(2006) - et al.
TAK1 is critical for IκB kinase-mediated activation of the NF-κB pathway
J Mol Biol
(2003) - et al.
Immune activation of NF-κB and JNK requires Drosophila TAK1
J Biol Chem
(2003) - et al.
TAK1 is a central mediator of NOD2 signaling in epidermal cells
J Biol Chem
(2008) - et al.
TLR8-mediated NF-κB and JNK activation are TAK1-independent and MEKK3-dependent
J Biol Chem
(2006) - et al.
The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes
Mol Cell
(2004)
A critical role of TAK1 in B cell receptor-mediated NF-κB activation
Blood
Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO
Mol Cell
TAB2 and TAB3 activate the NF-κB pathway through binding to polyubiquitin chains
Mol Cell
The CARMA1-Bcl10 signaling complex selectively regulates JNK2 kinase in the T cell receptor-signaling pathway
Immunity
Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway
J Biol Chem
A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK
Cell
Gadd45 is not required for activation of c-Jun N-terminal kinase or p38 during acute stress
J Biol Chem
Stress-induced JNK activation is independent of Gadd45 induction
J Biol Chem
GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells
Immunity
Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. v
J Biol Chem
Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis–CREB and NF-κB as key regulators
Immunity
Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 Cells
J Biol Chem
The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38
J Biol Chem
Feedback control of MKP-1 expression by p38
Cell Signal
ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin–proteasome pathway
J Biol Chem
Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling
J Biol Chem
Inflammatory signals in dendritic cell activation and the induction of adaptive immunity
Immunol Rev
A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways
Nat Rev Immunol
Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation
J Leukoc Biol
Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation
Physiol Rev
Integrated activation of MAP3Ks balances cell fate in response to stress
J Cell Biochem
The many paths to p38 mitogen-activated protein kinase activation in the immune system
Nat Rev Immunol.
Dual-specificity MAP kinase phosphatases (MKPs) and cancer
Cancer Metastasis Rev
Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases
Oncogene
MAPK phosphatases–regulating the immune response
Nat Rev Immunol
MAP kinases in immune response
Annu Rev Immunol
Regulation of the immune response by stress-activated protein kinases
Immunol Rev
The specificities of protein kinase inhibitors: an update
Biochem J
The selectivity of protein kinase inhibitors; a further update
Biochem J
Ubiquitin-mediated activation of TAK1 and IKK
Oncogene
Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction
Science
The kinase TAK1 can activate the NIK-I κB as well as the MAP kinase cascade in the IL-1 signalling pathway
Nature
Mutations in the Drosophila dTAK1 gene reveal a conserved function for MAPKKKs in the control of rel/NF-κB-dependent innate immune responses
Genes Dev
The TGF beta activated kinase TAK1 regulates vascular development in vivo
Development
TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo
Genes Dev.
Essential function for the kinase TAK1 in innate and adaptive immune responses
Nat Immunol
A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-κB activation
Embo J
The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function
Nat Immunol
TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells
Int Immunol
Essential role of TAK1 in thymocyte development and activation
Proc Natl Acad Sci USA
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