Germinal center kinases (GCKs) participate in a variety of signaling pathways needed to regulate cellular functions including apoptosis, cell proliferation, polarity and migration. Recent studies have shown that GCKs are participants in both adaptive and innate immune regulation. However, the differential activation and regulatory mechanisms of GCKs, as well as upstream and downstream signaling molecules, remain to be fully defined. It remains unresolved whether and how GCKs may cross-talk with existing signaling pathways. This review stresses the progresses in research of GCKs relevant to the immune system.
Germinal center kinases (GCKs) are a family of ‘Sterile 20 (STE20) like kinases’, which participate in both the determination of cell fate and the regulation of cell functions. Functions of GCKs are linked with human diseases including cancer and immunological disorders. Emerging studies indicate that certain GCKs, especially members of GCK-I, GCK-II, GCK-III, GCK-VI and GCK-VIII subfamilies, are involved in inflammatory responses and are possibly components of the response to virus infection (Figure 1). However, the molecular and atomic aspects of GCK activation and regulation are not fully understood. Here we summarize recent studies on GCKs with a special focus on their functional roles in immune regulation.
GCK-I kinases regulate NF-κB activation, integrin activity, pathogen-associated molecular pattern signaling and inflammation
GCK-I kinases are mitogen-activated protein kinase (MAPK) kinase kinase kinases that are termed MAP4Ks. GCK-I kinases can activate extracellular signal-regulated kinase, c-jun N-terminal kinase (c-JNK) and p38 signaling cascades to regulate cell proliferation and apoptosis upon extracellular stimuli.1
MAP4K1, also known as the hematopoietic progenitor kinase 1, is highly expressed in bone marrow, spleen and thymus. MAP4K1 may associate with a range of adaptor molecules, including growth factor receptor bound protein 2 (Grb2), the non-catalytic region of tyrosine kinase (Nck), the v-crk sarcoma virus CT10 oncogene homolog, the Src Homology 2 domain containing leukocyte protein of 76 kD (SLP-76) and the hematopoietic progenitor kinase 1-interacting protein of 55 kDa (HIP-55), to participate in the regulation of signaling pathways mediated by diverse structures such as the antigen receptor, epidermal growth factor receptor and IkappaB kinases.2,3
Intact holokinase MAP4K1 mediates T-cell receptor (TCR)-induced activation of nuclear factor of kappa light chain in B cells (NF-κB) through phosphorylation of the adaptor protein caspase recruitment domain containing protein 11 (CARMA1).4 Upon TCR stimulation, SLP-76 interacts with and activates MAP4K3, which directly activate protein kinase C (PKC)-theta, leading to NF-κB activation.5 MAP4K3-deficient mice showed resistance to experimental autoimmune encephalomyelitis.
While full-length MAP4K1 activates both JNK and NF-κB signaling, the C-terminal domain which results from caspase 3 cleavage can function as a suppressor of NF-κB activation and anti-apoptotic B-cell lymphoma protein 2 proteins.6,7,8,9
The adhesion and degranulation promoting adaptor protein (ADAP) forms a complex with Src kinase-associated phosphoprotein 55 kD (SKAP55) and Ras-associated protein 1 (Rap1)-GTP-interacting adaptor molecule (RIAM). ADAP binds to SLP-76 in a TCR-stimulation dependent manner to translocate the ADAP–SKAP55–RIAM complex to the cell membrane and further recruit the active small GTPase Rap1. Activation of Rap1, via interaction with the regulator for cell adhesion and polarization enriched in lymphoid tissues (RapL), regulates the integrin activity of leukocyte function associated antigen 1 (LFA-1) to alter T-cell adhesion.
Recent studies have revealed that MAP4K1 may compete with ADAP for SLP-76 binding and thus negatively regulate integrin activity.10 A similar observation concerning B-cell adhesion, involving MAP4K1, SKAP55 homolog and RIAM, has been reported.11 It is worth noting that GCK-II subfamily members MST1 and MST2 (see more below), can also interact with RapL,12 raising the possibility that GCK-II kinases regulate integrin activation independent of SLP-76 pathway.
MAP4K2 has also been implicated in the regulation of vesicle targeting or fusion.13 More recently, MAP4K2 is reported to play an essential role in pathogen-associated molecular pattern signaling and systemic inflammation through JNK and p38 pathways.14 Upon pathogen-associated molecular pattern stimulation, MAP4K2 can form a complex with tumor-necrosis factor receptor associated factor 6 and mixed lineage protein kinase 3, which stabilize MAP4K2 to activate JNK/p38 for competent innate immune response. The common adaptor, myeloid differentiation primary response protein (MyD88), is shown to be involved in the recruitment of effector molecules during this pro-inflammatory signaling process.
GCK-II kinases regulate lymphocyte adhesion, migration, proliferation and apoptosis
The Hippo (Hpo) pathway was initially identified in drosophila as a critical regulator for organ size control.15 Compared to NOTCH signaling, Hedgehog signaling and Wnt signaling, the relatively novel Hpo pathway is currently undergoing extensive investigation. The core components of Hpo pathway include Hpo, Warts, Sav and Mats, all of which are highly conserved (Figure 2).16 MST1 and MST2, which are highly abundant in lymphoid tissues, are mammalian homologs of drosophila ‘Hpo’. Sav, Ras-association domain family protein (Rassf), and Hpo share similar dimerization regions called SARAH domains.
The C-terminal SARAH domains of MST1/2 can mediate an inhibitory effect on kinase activation. It is thought that MST1/2 may associate with many adaptor molecules including Sav and Rassf through SARAH domain-mediated heterodimerization. We and others have recently determined the SARAH domain of MST1/2 as an antiparallel dimeric conformation,17 providing mechanistic understanding of MST1/2 self-inhibition and activation. In addition, MST1 may be differentially targeted by different caspases to activate distinct MAPK pathways.18,19,20,21,22,23
MST1 has been implicated in T-cell biology, as mice lacking MST1 exhibit a variety of T-cell abnormalities.24 Cross-talk between MST1 and Akt appears able to antagonize Akt1 activity,25 which is involved in T-cell costimulation and the regulation of NF-κB-dependent gene transcription. MST1 negatively regulates the activation and proliferative response of naive T cells.26 A 10-fold reduction of MST1 level has been observed for the normal transition from naive to effector cells. Upon TCR stimulation, naive T cells deficient in MST1 exhibit stronger proliferative responses, as well as higher apoptosis levels.
Moreover, MST1–FOXO signaling is important for peripheral naive T-cell homeostasis upon apoptotic stimuli.27 MST1-deficient T cells showed downregulation of FOXO1 expression and upregulation of FAS expression.28 Recently, it was reported that patients lacking MST1 displayed primary immunodeficiency like features.29 MST1 was found to be critical for maintenance of lymphocytes and control of unrestricted Epstein–Barr virus(EBV)-induced lymphoproliferation. However, the exact mechanism by which MST1 restricts improper proliferation of naive and mature T cells remains enigmatic.
Animal studies indicate that MST1 plays a critical role in lymphocyte chemotaxis and thymocyte emigration.30 MST1 is involved in the regulation of immune cell polarity and adhesion through Rap1–RapL signaling pathway via its direct interaction with RapL or RIAM.12,31 Upon chemokine or TCR activation, RapL binds to and alters MST1 cellular localization and kinase activity, followed by induction of polarized morphology and integrin LFA-1 clustering at the leading edge. Deficiency in either RAPL or MST1 impairs LFA-1 clustering in T cells.26,32 The biochemical mechanism by which MST1 promotes LFA-1 activation is currently unknown.
Furthermore, MST1 controls lymphocyte trafficking and interstitial migration, which is important for efficient immunosurveillance and effective immune responses.32 MST1/2 may control Rho GTPase activation and mature T cells egress from the thymus by activating Dock8.24 In MST1 and MST2 double knockout mice, mature T cells cannot efficiently migrate from thymus to the circulation and secondary lymphoid organs. While T cells can develop normally in these double knockout mice, the apoptotic rate of CD4+CD8− and CD4−CD8+ single-positive thymocytes is dramatically increased.
Transforming growth factor-beta (TGF-β) is a multifunctional protein that plays an important role in the immune system by regulation of Foxp3+ regulatory T cells and Th17 cells. Death-associated protein 6 (Daxx) plays a major role in TGF-β signaling by interaction with type II TGF-β receptor kinase.33 As a novel histone chaperone and a product of an interferon-γ-induced gene, Daxx has been extensively implicated in virus infection and T-cell activation.34,35,36,37,38,39,40,41,42,43 Recent studies demonstrated that MST1 and Daxx interact with each other to mediate interferon-γ-induced apoptosis in microglia, which plays a critical role during inflammation.44 In this process, Daxx directly binds to MST1 and regulates its homo-oligomerization, activation and nuclear translocation. It is interesting that both MST1 and Daxx have been observed to associate with mitotic checkpoint protein Rassf1.44,45 In addition, Ferritin heavy chain (FTH1) may bind directly with Daxx to regulate apoptosis.46 At this point, it remains unknown how Daxx mechanistically regulates the activity and cellular localization of MST1 and how MST1 and Daxx may interplay with Rassf1 and FTH1.
MST1 activity may be influenced by the oxidative environment changes in inflammatory sites. Peroxiredoxins were initially characterized as endogenous antioxidant enzymes important for protecting cells from oxidative damage. Beyond their catalytic activities, peroxiredoxins have been recently identified to function as chaperones or adaptors in inflammation, cancer and innate immunity.47 For example, peroxiredoxin 1 (PRX-I) may interact with Toll-like receptor 4 (TLR4) to activate NF-κB and other signaling pathways during inflammatory responses. Moreover, TGF-β may stimulate some cells to secrete PRX-I proteins, which then enhance natural killer cell activity and suppress virus replication. A recent study of PRX-I in H2O2-induced apoptosis revealed that PRX-I may directly interact with MST1 to stimulate its kinase activity.48 During this process, elevated levels of H2O2 can promote clustering of PRX-I to form high-order oligomers, likely decamers.49,50 The doughnut-shaped homodecamers of PRX-I would then specifically bind to MST1 and remove the inhibitory effect of its C-terminal region, leading to activation of MST1. Further biochemical and structural studies would help to fully understand the correlation between cellular redox environment and the PRX-I-related activation of MST1 and possibly other GCKs.
The crystal structures of the MST1 N-terminal kinase domain and C-terminal dimerization domain have been determined.17 We and others have shown that both kinase domain mediated dimerization and C-terminus-mediated dimerization are required for the activation of Hpo or MST1.17,51 Structural information of the full-length MST1/2 and complexes with Sav, RapL, Daxx and PRX-I should provide an in-depth mechanistic dissection of the MST1/2 activation and regulation, which together with mutational analysis would strongly support further functional studies of the MST1/2 signaling pathway.
GCK-III kinases as immerging novel immune regulators
There are three members of the GCK-III subfamily including MST3, MST4 and STK25. GCK-III has been implicated in cell adhesion, apoptosis and polarity regulation (Figure 3). Whether GCK-III kinases activate MAPK signaling remains unclear. While MST3 is involved in apoptosis,52 STK25 is involved in cell migration and adhesion.53,54,55 MST4 was identified as a novel member of the GCK family of STE20 kinases in 2001 and was found to be highly expressed in placenta, thymus and peripheral blood leukocytes.56,57
The structures of the kinase domains have been determined yet the biological functions of GCK-III in particular remain elusive. In fact, the exact activation mechanism of GCK-III and the function of their C-terminal domains have not been clearly defined. For example, the biological importance of MST4a, an alternatively spliced isoform that is highly expressed in early stages of development, is not well understood. GCK-III kinases share a group of common regulatory proteins including MO25, programmed cell death 10 (PDCD10), the Golgi matrix protein of 130 kDa (GM130) and Striatin. Here we summarize the known interactions between GCK-III and these factors and analyze their potential functional relevance to immune regulation.
MO25 and PDCD10 are direct regulators of GCK-III
MO25 is an adaptor protein that appears to interact with the tumor suppressor liver kinase B1 (LKB1) and the pseudo-kinase STRAD to form a ternary complex.58,59,60,61,62 The ‘horse-shoe’ shaped MO25 functions as a scaffold to stabilize the interaction between LKB1 and STRAD. Consequently, LKB1 is retained in the cytoplasm and its kinase activity is enhanced. As a major upstream regulator of AMP-activated protein kinase subfamily members, including MARK/Par-1, LKB1 is involved in multiple aspects of cell function and has been linked to many human diseases especially malignant tumors.63,64,65,66,67,68,69,70,71
Recently, LKB1 has been implicated in B-cell differentiation by mediating activation-induced cytidine deaminase-dependent remodeling of immunoglobulin genes,72 as well as in T-cell differentiation by regulating TCR-mediated activation of phospholipase C gamma1 and AMP-activated protein kinase signaling.73,74 LKB1 is directly phosphorylated by lymphocyte-specific protein tyrosine kinase and predominantly interacts with the adaptor protein LAT as well as phospholipase C gamma1 following TCR stimulation. Moreover, the LKB1 substrate AMP-activated protein kinase has lately been demonstrated to play a role in antiviral defenses by restricting fatty acid synthesis that is required for the replication of many RNA viruses.75
In addition to associating with LKB1, MO25 can also bind to and activate GCK-III and GCK-VI kinases.76 Both previous studies and our unpublished data indicate that GCK-III kinases could interact or associate with MO25, STRAD and LKB1, forming a dynamic complex in cells.59 We also observed that GCK-III appears to phosphorylate STRAD and negatively regulates NF-κB activation. Taken together, GCK-III signaling may cross-talk with LKB1 signaling through their shared coregulators such as MO25 (Figure 3).
PDCD10, a regulator of cell growth and migration, has been implicated in normal cardiovascular development as well as certain human pathologies.54,77,78 The N-terminal domain of PDCD10 mediates homodimerization while the C-terminal domain structurally resembles the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK).79 Constitutive expression of PDCD10 in peripheral blood T-cells has been correlated with cutaneous T-cell lymphoma.80 The homodimers of PDCD10 and GCK-III may undergo dissociation and form a PDCD10–GCK-III heterodimer, which stabilizes and activates GCK-III.81 Moreover, PDCD10 can associate with Striatin through its C-terminal FAT domain, which then recruits GCK-III to the so-called Striatin-interacting phosphatase and kinase (‘STRIPAK’) complex containing not only kinase but also phosphotase such as protein phosphatase 2.82 Meanwhile, Striatin can also bind to calmodulin (a calcium-binding protein that regulates the functions of many kinases), phosphotases, ion channels and other proteins in a calcium-dependent manner.83,84,85 We have postulated that PDCD10 may cross-talk with FAK.
FAK has been implicated in innate immune responses especially antivirus signaling.86,87,88 FAK consists of an N-terminal FERM domain, a tyrosine kinase domain, a proline-rich region and a C-terminal FAT domain. The FERM domain interacts with the kinase domain, leading to autoinhibition of FAK. The activity, localization and downstream signaling of FAK are regulated by its interactions with other partners through the FERM, proline-rich and FAT domains.89,90 FAK is involved in integrin signaling, cytoskeletal remodeling, cell polarity and migration.89 FAK is involved with TLR-induced MyD88 signaling, which plays a role in initiating innate immune responses.87 FAK and CD4 have been implicated in a signaling complex in T cells stimulated by the HIV protein gp120.88 The FAT domain binds to the CD4 endocytosis motif, which limits lymphocyte-specific protein tyrosine kinase binding to CD4.
HIV gp120 can facilitate FAK binding to CD4 in T cells. It was further suggested that HIV protein Nef competes with FAK for CD4 binding, preventing apoptosis of the infected cells. A recent study of FAK in virus infection revealed that FAK may function as a link between cytoskeletal alterations induced by virus infection and activation of mitochondrial antiviral signaling adaptor (MAVS)-mediated antiviral signaling.86 Upon virus infection, FAK interacts with MAVS in the mitochondrial membrane to promote MAVS-mediated antiviral signaling in a manner independent of FAK kinase activity.
We have found that PDCD10 can not only interact with paxillin but also may bind to the cytoplasmic domain of CD8 and CD4 (unpublished data). As mentioned, FAK, CD4 and CD8 play vital roles in cell signaling during immune responses and regulations. As a component of the STRIPAK complex, PDCD10 may be phosphorylated by GCK-III, which raises the possibility that GCK-III may regulate the association of PDCD10 with other proteins. PDCD10 can bind to and stabilize GCK-III kinases, as well as promoting their kinase activities.78 The N-terminal homodimerization domain of PDCD10 can form a stable heterodimer with the C-terminal homodimerization domain of GCK-III, indicating that GCK-III and PDCD10 may function together as a complex.
MO25 and PDCD10 appear to bind to and regulate the activity of GCK-III. Recently, we have determined the structural mechanism by which MO25 stimulates the activation of GCKIII, as well as structurally characterized the GCK-III–PDCD10 complexes (unpublished data). The potential function of MO25–GCK-III–PDCD10 signaling in immune regulation, as well as to detect possible cross-talk with existing pathways, such as LKB1, FAK and MAVS-mediated signaling, remain of interest to our laboratory.
GM130 and Striatin may regulate GCK-III phosphorylation and cellular localization
GM130 is a Golgi matrix protein largely consisting of coiled-coil domains, which functions to maintain the structural integrity of Golgi.91,92,93 The very C-terminus of GM130 may bind to and stimulate the catalytic activity of HtrA1, a serine protease that inhibits TGF-β signaling.94 EspG proteins produced by enteric pathogens may interact with GM130 and disrupt protein secretion of the host cells.95 GCK-III kinases may target the Golgi apparatus through binding with GM130 (Figure 3).53,96 Despite forming a stable complex, PDCD10 and Striatin may differentially regulate GCK-III. For example, PDCD10 knockdown promotes Golgi localization of MST4 in HeLa cells. On the contrary, knockdown of Striatin impaired MST4 localization to Golgi. Given that Striatin is a component of the protein phosphatase 2 holo enzyme, it is likely that high levels of Striatin would decrease the phosphorylation level of MST4, leading to inactive conformation.
As mentioned, PDCD10 has been reported to enhance the activation of MST4.78,81 We therefore hypothesize that the Golgi matrix protein GM130 might recruit MST4 depending on the phosphorylation and activation status of MST4. It is worth noting that the STRIPAK complex may also interact with GCK-II kinases MST1/2 and GCK-IV kinase misshapen/NIK-related kinase.97,98 Thus, it remains an open question whether PDCD10 and GCK-III as components of the STRIPAK complex could cross-talk with GCK-II and GCK-IV signaling pathways.
Ezrin–radixin–moesin (ERM) proteins are direct substrates of GCK-III
ERM proteins function as linkers between the plasma membrane and the cytoskeleton, and are relevant for transduction of immune signals across the cell membrane. ERM proteins are recruited to membrane regions where PIP2 binds to and triggers conformational changes of the ERM species, leading to the phosphorylation of a conserved threonine in their actin-binding domain.99 ERM proteins act as a scaffold for cAMP signaling pathways which couple a G-protein coupled receptor to multiple functional aspects including proliferation, apoptosis, adhesion and migration.100,101 ERM proteins are directly involved in the formation of the immunological synapse, a critical event during T-cell activation.
Loss of Ezrin has been correlated with decreased IL-2 production,102,103,104 as well as with impaired migration of T-cell signaling microclusters consisting of TCR and downstream signaling components.105 Moreover, ERM proteins also play a role in cAMP-mediated T-cell repression by regulating PKA signaling.106,107 In addition to Rho, PKCα and PKCθ, recent studies have identified several GCK family members including MST1, MST4, NCK-interacting kinase (NIK) and lymphocyte-oriented kinase (LOK) as upstream kinases that can directly phosphorylate ERM. GCK kinases could regulate aspects of the potency of immune responses through phosphorylation of ERM proteins (Figure 3). Further study attempting to define an immunological role of the GCK-III kinases is in progress.
GCK-VI kinases contribute to regulation of T-cell activation
GCK-VI kinases include oxidative stress-responsive 1 (OSR1) and SPAK, both of which have undetectable constitutive activities. During T-cell activation, SPAK is involved in TCR/CD28-induced AP-1 activation through interactions with the PKCθ molecule via its C-terminal region.108 Receptor expressed in lymphoid tissues and its homologs RELL1 and RELL2 are non-canonical members of TNFR family that may be distinct from those of classical members in terms of signaling. The C-terminal domain of SPAK/OSR1 may bind to the ‘RFRV’ motif found in the cytoplasmic domain of receptor expressed in lymphoid tissue subfamily members, leading to phosphorylation of receptor expressed in lymphoid tissue and downstream signaling.109,110 Interestingly, the activity of SPAK can be downregulated by the TNF family member TRAIL, indicating a potential role in immune regulation.111
OSR1 has recently been identified as a key regulator of ion homeostasis and cell volume downstream of the WNK signaling pathway.112,113,114,115,116 OSR1 and SPAK target the Na–K–Cl cotransporter. MO25 is a potent regulator of OSR1 kinase activity.76 In addition, we have found that OSR1 is self-inhibited and MO25 association with OSR1 is dependent on site-specific phosphorylation of OSR1. Moreover, the kinase activity of OSR1 is subject to differential regulation of cations including Mg2+ and Mn2+ (unpublished data). OSR1 may regulate T-cell activation through control of osmotic pressure. Therefore, it would be intriguing to correlate the kinase activity of OSR1 to ion homeostasis and T-cell activation.
Our preliminary studies suggest that the regulatory mechanism of GCK-VI activation is likely a coordinated process between MO25 and other yet-to-be identified factors. To date, fragments of the kinase domain and the C-terminal domain of OSR1 have been structurally characterized.117,118,119 However, the overall full-length structures of GCK-VI, as well as the structures of their complexes with MO25, are still not available. Given that low-level activity has been significantly hindering the functional study of GCK-VI, combined biochemical and structural studies that dissect the kinase activation mechanism are necessary to facilitate further functional investigation of GCK-VI in T-cell activation.
Other GCKs relevant to immune regulation
The GCK-IV subfamily member misshapen/NIK-related kinase, a novel component of the STRIPAK complex,98 is highly expressed in hematopoietic tissues and can activate the JNK signaling pathway.120 The expression of NIK, another GCK-IV subfamily member can be selectively stimulated by TNF-α through a TNFR1-dependent mechanism.121 RNA interference targeting macrophage NIK protected mice from lipopolysaccharide-induced lethality by preventing TNF-α and IL-1β secretion.122 The GCK-V subfamily member LOK is a 130-kDa serine/threonine kinase predominantly expressed in lymphoid tissues.123 LOK does not activate MAPK signaling but is involved in LFA-1-mediated lymphocyte adhesion.124 SLK, which is similar to LOK, can regulate focal adhesion turnover through unknown mechanism that involves FAK.125,126,127
The GCK-VIII subfamily member TAO2 is a mitogen-activated protein kinase kinase kinase which associates with and activates MAPK/extracellular signal-regulated kinase kinase 3 (MEK3) and MEK6 to activate p38.128 Since p38 regulates the expression of inflammatory cytokines, TAO2 may be considered for therapeutic targeting for diseases such as autoimmunity. For example, TAO2 can associate with TGF-β activated kinase 1 (TAK1) to inhibit TAK1-mediated activation of NF-κB.129 TAO2 may regulate TAK1 function through interfering with the interaction between TAK1 and IkappaB kinase. Furthermore, TAO2 does not inhibit the activation of JNK by TAK1, suggesting that TAO2 regulation of TAK1 is important to activate specific intracellular signaling pathways.
GCKs are important immune regulators, but their activation mechanisms and functional regulation remain incompletely understood. It is likely that targeted therapeutics may modify both activation and regulation of these kinases. Combined structural and functional characterization of GCKs is required to further elucidate their roles in immune regulation and inflammation.
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This work was supported by the 973 Program of the Ministry of Science and Technology of China (2010CB529700 and 2012CB910204), the National Natural Science Foundation of China (NSFC10979005 and NSFC30970566) and the Science and Technology Commission of Shanghai Municipality (11JC14140000). Dr ZZ is a scholar of the Hundred Talents Program of the Chinese Academy of Sciences. Dr Greene is supported by grants from the NIH, NCI, the Abramson Family Research Institute and the BCRF.
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Yin, H., Shi, Z., Jiao, S. et al. Germinal center kinases in immune regulation. Cell Mol Immunol 9, 439–445 (2012). https://doi.org/10.1038/cmi.2012.30
- germinal center kinases
- immune regulation
- signal transduction
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