Germinal Center Kinases in Immune Regulation

REVIEW

Germinal center kinases in immune regulation

Hailei Yin1,2, Zhubing Shi3, Shi Jiao3, Cuicui Chen3, Wenjia Wang3, Mark I Greene4 and Zhaocai Zhou3

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. Cellular & Molecular Immunology (2012) 9, 439–445; doi:10.1038/cmi.2012.30; published online 10 September 2012

Keywords: germinal center kinases; immune regulation; signal transduction

INTRODUCTION (NF-kB) through phosphorylation of the adaptor protein caspase Germinal center kinases (GCKs) are a family of ‘Sterile 20 (STE20) like recruitment domain containing protein 11 (CARMA1).4 Upon TCR kinases’, which participate in both the determination of cell fate and stimulation, SLP-76 interacts with and activates MAP4K3, which directly the regulation of cell functions. Functions of GCKs are linked with activate protein kinase C (PKC)-theta, leading to NF-kB activation.5 human diseases including cancer and immunological disorders. MAP4K3-deficient mice showed resistance to experimental autoimmune Emerging studies indicate that certain GCKs, especially members of encephalomyelitis. GCK-I, GCK-II, GCK-III, GCK-VI and GCK-VIII subfamilies, are While full-length MAP4K1 activates both JNK and NF-kB signal- involved in inflammatory responses and are possibly components of ing, the C-terminal domain which results from caspase 3 cleavage can the response to virus infection (Figure 1). However, the molecular and function as a suppressor of NF-kB activation and anti-apoptotic B-cell atomic aspects of GCK activation and regulation are not fully under- lymphoma protein 2 proteins.6–9 stood. Here we summarize recent studies on GCKs with a special focus The adhesion and degranulation promoting adaptor protein on their functional roles in immune regulation. (ADAP) forms a complex with Src kinase-associated phosphoprotein 55 kD (SKAP55) and Ras-associated protein 1 (Rap1)-GTP-interacting GCK-I KINASES REGULATE NF-kB ACTIVATION, INTEGRIN adaptor molecule (RIAM). ADAP binds to SLP-76 in a TCR-stimulation ACTIVITY, PATHOGEN-ASSOCIATED MOLECULAR PATTERN dependent manner to translocate the ADAP–SKAP55–RIAM complex SIGNALING AND INFLAMMATION to the cell membrane and further recruit the active small GTPase Rap1. GCK-I kinases are mitogen-activated protein kinase (MAPK) kinase Activation of Rap1, via interaction with the regulator for cell adhesion kinase kinases that are termed MAP4Ks. GCK-I kinases can activate and polarization enriched in lymphoid tissues (RapL), regulates the extracellular signal-regulated kinase, c-jun N-terminal kinase (c-JNK) integrin activity of leukocyte function associated antigen 1 (LFA-1) to and p38 signaling cascades to regulate cell proliferation and apoptosis alter T-cell adhesion. upon extracellular stimuli.1 Recent studies have revealed that MAP4K1 may compete with MAP4K1, also known as the hematopoietic progenitor kinase 1, is ADAP for SLP-76 binding and thus negatively regulate integrin acti- highly expressed in bone marrow, spleen and thymus. MAP4K1 may vity.10 A similar observation concerning B-cell adhesion, involving associate with a range of adaptor molecules, including growth factor MAP4K1, SKAP55 homolog and RIAM, has been reported.11 It is receptor bound protein 2 (Grb2), the non-catalytic region of tyrosine worth noting that GCK-II subfamily members MST1 and MST2 (see kinase (Nck), the v-crk sarcoma virus CT10 oncogene homolog, the more below), can also interact with RapL,12 raising the possibility that Src Homology 2 domain containing leukocyte protein of 76 kD (SLP- GCK-II kinases regulate integrin activation independent of SLP-76 76) and the hematopoietic progenitor kinase 1-interacting protein of pathway. 55 kDa (HIP-55), to participate in the regulation of signaling pathways MAP4K2 has also been implicated in the regulation of vesicle tar- mediated by diverse structures such as the antigen receptor, epidermal geting or fusion.13 More recently, MAP4K2 is reported to play an growth factor receptor and IkappaB kinases.2,3 essential role in pathogen-associated molecular pattern signaling Intact holokinase MAP4K1 mediates T-cell receptor (TCR)- and systemic inflammation through JNK and p38 pathways.14 Upon induced activation of nuclear factor of kappa light chain in B cells pathogen-associated molecular pattern stimulation, MAP4K2 can 1Department of Trauma and Orthopaedics, General Hospital of Jinan Military Region, Jinan, China; 2No. 401 Hospital of People Liberation Army, Qingdao, China; 3State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China and 4Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA Correspondence: Dr ZC Zhou, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, 320 Yueyang Road, Shanghai 200031, China. E-mail: [email protected] Received 3 August 2012; accepted 4 August 2012 GCKs in immune regulation HL Yin et al 440

others have recently determined the SARAH domain of MST1/2 as an antiparallel dimeric conformation,17 providing mechanistic under- standing of MST1/2 self-inhibition and activation. In addition, MST1 may be differentially targeted by different caspases to activate distinct MAPK pathways.18–23 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-kB-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 stron- ger proliferative responses, as well as higher apoptosis levels. Moreover, MST1–FOXO signaling is important for peripheral Figure 1 GCKs in immune regulation. GCK, germinal center kinase. naive T-cell homeostasis upon apoptotic stimuli.27 MST1-deficient form a complex with tumor-necrosis factor receptor associated factor T cells showed downregulation of FOXO1 expression and upregula- tion of FAS expression.28 Recently, it was reported that patients lack- 6 and mixed lineage protein kinase 3, which stabilize MAP4K2 29 to activate JNK/p38 for competent innate immune response. The ing MST1 displayed primary immunodeficiency like features. MST1 common adaptor, myeloid differentiation primary response protein was found to be critical for maintenance of lymphocytes and control (MyD88), is shown to be involved in the recruitment of effector mole- of unrestricted Epstein–Barr virus(EBV)-induced lymphoprolifera- cules during this pro-inflammatory signaling process. tion. However, the exact mechanism by which MST1 restricts improper proliferation of naive and mature T cells remains enigmatic. GCK-II KINASES REGULATE LYMPHOCYTE ADHESION, Animal studies indicate that MST1 plays a critical role in lympho- 30 MIGRATION, PROLIFERATION AND APOPTOSIS cyte chemotaxis and thymocyte emigration. MST1 is involved in the The Hippo (Hpo) pathway was initially identified in drosophila as a regulation of immune cell polarity and adhesion through Rap1–RapL 12,31 critical regulator for organ size control.15 Compared to NOTCH sig- signaling pathway via its direct interaction with RapL or RIAM. naling, Hedgehog signaling and Wnt signaling, the relatively novel Upon chemokine or TCR activation, RapL binds to and alters MST1 Hpo pathway is currently undergoing extensive investigation. The cellular localization and kinase activity, followed by induction of core components of Hpo pathway include Hpo, Warts, Sav and polarized morphology and integrin LFA-1 clustering at the leading Mats, all of which are highly conserved (Figure 2).16 MST1 and edge. Deficiency in either RAPL or MST1 impairs LFA-1 clustering 26,32 MST2, which are highly abundant in lymphoid tissues, are mam- in T cells. The biochemical mechanism by which MST1 promotes malian homologs of drosophila ‘Hpo’. Sav, Ras-association domain LFA-1 activation is currently unknown. family protein (Rassf), and Hpo share similar dimerization regions Furthermore, MST1 controls lymphocyte trafficking and interstitial called SARAH domains. migration, which is important for efficient immunosurveillance and 32 The C-terminal SARAH domains of MST1/2 can mediate an inhi- effective immune responses. MST1/2 may control Rho GTPase bitory effect on kinase activation. It is thought that MST1/2 may activation and mature T cells egress from the thymus by activating associate with many adaptor molecules including Sav and Rassf Dock8.24 In MST1 and MST2 double knockout mice, mature T cells through SARAH domain-mediated heterodimerization. We and cannot efficiently migrate from thymus to the circulation and second- ary lymphoid organs. While T cells can develop normally in these double knockout mice, the apoptotic rate of CD41CD82 and CD42CD81 single-positive thymocytes is dramatically increased. Transforming growth factor-beta (TGF-b) is a multifunctional protein that plays an important role in the immune system by regulation of Foxp31 regulatory T cells and Th17 cells. Death- associated protein 6 (Daxx) plays a major role in TGF-b signaling by interaction with type II TGF-b receptor kinase.33 As a novel histone chaperone and a product of an interferon-c-induced gene, Daxx has been extensively implicated in virus infection and T-cell activation.34–43 Recent studies demonstrated that MST1 and Daxx interact with each other to mediate interferon-c-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 interes- ting 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 Figure 2 GCK-II signaling network. DAXX, death-associated protein 6; GCK, germinal center kinase; MAPK, mitogen-activated protein kinase; PP2A, protein At this point, it remains unknown how Daxx mechanistically re- phosphatase 2; PRX-1, peroxiredoxin 1; Rap1, Ras-related protein 1; RapL, gulates the activity and cellular localization of MST1 and how MST1 regulator for cell adhesion and polarization enriched in lymphoid tissues. and Daxx may interplay with Rassf1 and FTH1.

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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-kB and other signaling pathways during inflammatory responses. Moreover, TGF-b 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 under- Figure 3 GCK-III and its regulators. ERM, ezrin–radixin–moesin; FAK, focal stand the correlation between cellular redox environment and the adhesion kinase; GCK, germinal center kinase; LKB1, liver kinase B1; MAPK, PRX-I-related activation of MST1 and possibly other GCKs. mitogen-activated protein kinase; PDCD10, programmed cell death 10; PP2A, The crystal structures of the MST1 N-terminal kinase domain and protein phosphatase 2. C-terminal dimerization domain have been determined.17 We and LKB1 is involved in multiple aspects of cell function and has been others have shown that both kinase domain mediated dimerization 63–71 and C-terminus-mediated dimerization are required for the activation linked to many human diseases especially malignant tumors. of Hpo or MST1.17,51 Structural information of the full-length MST1/ Recently, LKB1 has been implicated in B-cell differentiation by mediating activation-induced cytidine deaminase-dependent remo- 2 and complexes with Sav, RapL, Daxx and PRX-I should provide an 72 in-depth mechanistic dissection of the MST1/2 activation and regu- deling of immunoglobulin genes, as well as in T-cell differentiation lation, which together with mutational analysis would strongly sup- by regulating TCR-mediated activation of phospholipase C gamma1 73,74 port further functional studies of the MST1/2 signaling pathway. and AMP-activated protein kinase signaling. LKB1 is directly phosphorylated by lymphocyte-specific protein tyrosine kinase and predominantly interacts with the adaptor protein LAT as well as phos- GCK-III KINASES AS IMMERGING NOVEL IMMUNE REGULATORS pholipase C gamma1 following TCR stimulation. Moreover, the LKB1 substrate AMP-activated protein kinase has lately been demonstrated There are three members of the GCK-III subfamily including MST3, to play a role in antiviral defenses by restricting fatty acid synthesis that MST4 and STK25. GCK-III has been implicated in cell adhesion, is required for the replication of many RNA viruses.75 apoptosis and polarity regulation (Figure 3). Whether GCK-III kinases In addition to associating with LKB1, MO25 can also bind to and activate MAPK signaling remains unclear. While MST3 is involved in 76 apoptosis,52 STK25 is involved in cell migration and adhesion.53–55 activate GCK-III and GCK-VI kinases. Both previous studies and MST4 was identified as a novel member of the GCK family of STE20 our unpublished data indicate that GCK-III kinases could interact or associate with MO25, STRAD and LKB1, forming a dynamic complex kinases in 2001 and was found to be highly expressed in placenta, 59 thymus and peripheral blood leukocytes.56,57 in cells. We also observed that GCK-III appears to phosphorylate k The structures of the kinase domains have been determined yet STRAD and negatively regulates NF- B activation. Taken together, the biological functions of GCK-III in particular remain elusive. In GCK-III signaling may cross-talk with LKB1 signaling through their fact, the exact activation mechanism of GCK-III and the function shared coregulators such as MO25 (Figure 3). of their C-terminal domains have not been clearly defined. For PDCD10, a regulator of cell growth and migration, has been implicated in normal cardiovascular development as well as certain human example, the biological importance of MST4a, an alternatively 54,77,78 spliced isoform that is highly expressed in early stages of development, pathologies. The N-terminal domain of PDCD10 mediates is not well understood. GCK-III kinases share a group of common reg- homodimerization while the C-terminal domain structurally resem- ulatory proteins including MO25, programmed cell death 10 (PDCD10), bles the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK).79 Constitutive expression of PDCD10 in peripheral the Golgi matrix protein of 130 kDa (GM130) and Striatin. Here we 80 summarize the known interactions between GCK-III and these factors blood T-cells has been correlated with cutaneous T-cell lymphoma. and analyze their potential functional relevance to immune regulation. 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 MO25 and PDCD10 are direct regulators of GCK-III through its C-terminal FAT domain, which then recruits GCK-III to MO25 is an adaptor protein that appears to interact with the tumor the so-called Striatin-interacting phosphatase and kinase (‘STRIPAK’) suppressor liver kinase B1 (LKB1) and the pseudo-kinase STRAD to complex containing not only kinase but also phosphotase such as form a ternary complex.58–62 The ‘horse-shoe’ shaped MO25 func- protein phosphatase 2.82 Meanwhile, Striatin can also bind to calmo- tions as a scaffold to stabilize the interaction between LKB1 and dulin (a calcium-binding protein that regulates the functions of STRAD. Consequently, LKB1 is retained in the cytoplasm and its many kinases), phosphotases, ion channels and other proteins in a kinase activity is enhanced. As a major upstream regulator of AMP- calcium-dependent manner.83–85 We have postulated that PDCD10 activated protein kinase subfamily members, including MARK/Par-1, may cross-talk with FAK.

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FAK has been implicated in innate immune responses especially anti- protein GM130 might recruit MST4 depending on the phosphoryla- virus signaling.86–88 FAK consists of an N-terminal FERM domain, a tion and activation status of MST4. It is worth noting that the tyrosine kinase domain, a proline-rich region and a C-terminal FAT STRIPAK complex may also interact with GCK-II kinases MST1/2 domain. The FERM domain interacts with the kinase domain, leading and GCK-IV kinase misshapen/NIK-related kinase.97,98 Thus, it to autoinhibition of FAK. The activity, localization and downstream sig- remains an open question whether PDCD10 and GCK-III as compo- naling of FAK are regulated by its interactions with other partners through nents of the STRIPAK complex could cross-talk with GCK-II and the FERM, proline-rich and FAT domains.89,90 FAK is involved in integrin GCK-IV signaling pathways. signaling, cytoskeletal remodeling, cell polarity and migration.89 FAK is involved with TLR-induced MyD88 signaling, which plays a role in Ezrin–radixin–moesin (ERM) proteins are direct substrates of 87 initiating innate immune responses. FAK and CD4 have been impli- GCK-III cated in a signaling complex in T cells stimulated by the HIV protein ERM proteins function as linkers between the plasma membrane and 88 gp120. The FAT domain binds to the CD4 endocytosis motif, which the cytoskeleton, and are relevant for transduction of immune signals limits lymphocyte-specific protein tyrosine kinase binding to CD4. across the cell membrane. ERM proteins are recruited to membrane HIV gp120 can facilitate FAK binding to CD4 in T cells. It was regions where PIP2 binds to and triggers conformational changes of further suggested that HIV protein Nef competes with FAK for CD4 the ERM species, leading to the phosphorylation of a conserved threo- binding, preventing apoptosis of the infected cells. A recent study of nine in their actin-binding domain.99 ERM proteins act as a scaffold FAK in virus infection revealed that FAK may function as a link for cAMP signaling pathways which couple a G-protein coupled between cytoskeletal alterations induced by virus infection and activa- receptor to multiple functional aspects including proliferation, apop- tion of mitochondrial antiviral signaling adaptor (MAVS)-mediated tosis, adhesion and migration.100,101 ERM proteins are directly antiviral signaling.86 Upon virus infection, FAK interacts with MAVS involved in the formation of the immunological synapse, a critical in the mitochondrial membrane to promote MAVS-mediated anti- event during T-cell activation. viral signaling in a manner independent of FAK kinase activity. Loss of Ezrin has been correlated with decreased IL-2 produc- We have found that PDCD10 can not only interact with paxillin but tion,102–104 as well as with impaired migration of T-cell signaling also may bind to the cytoplasmic domain of CD8 and CD4 (unpub- microclusters consisting of TCR and downstream signaling compo- lished data). As mentioned, FAK, CD4 and CD8 play vital roles in cell nents.105 Moreover, ERM proteins also play a role in cAMP-mediated signaling during immune responses and regulations. As a component of T-cell repression by regulating PKA signaling.106,107 In addition to the STRIPAK complex, PDCD10 may be phosphorylated by GCK-III, Rho, PKCa and PKCh, recent studies have identified several GCK which raises the possibility that GCK-III may regulate the association of family members including MST1, MST4, NCK-interacting kinase PDCD10 with other proteins. PDCD10 can bind to and stabilize GCK- (NIK) and lymphocyte-oriented kinase (LOK) as upstream kinases III kinases, as well as promoting their kinase activities.78 The N-terminal that can directly phosphorylate ERM. GCK kinases could regulate homodimerization domain of PDCD10 can form a stable heterodimer aspects of the potency of immune responses through phosphorylation with the C-terminal homodimerization domain of GCK-III, indicating of ERM proteins (Figure 3). Further study attempting to define an that GCK-III and PDCD10 may function together as a complex. immunological role of the GCK-III kinases is in progress. MO25 and PDCD10 appear to bind to and regulate the activity of GCK-III. Recently, we have determined the structural mechanism by GCK-VI KINASES CONTRIBUTE TO REGULATION OF T-CELL which MO25 stimulates the activation of GCKIII, as well as structu- ACTIVATION rally characterized the GCK-III–PDCD10 complexes (unpublished GCK-VI kinases include oxidative stress-responsive 1 (OSR1) and SPAK, data). The potential function of MO25–GCK-III–PDCD10 signaling both of which have undetectable constitutive activities. During T-cell in immune regulation, as well as to detect possible cross-talk with activation, SPAK is involved in TCR/CD28-induced AP-1 activation existing pathways, such as LKB1, FAK and MAVS-mediated signaling, throughinteractionswiththePKCh molecule via its C-terminal region.108 remain of interest to our laboratory. Receptor expressed in lymphoid tissues and its homologs RELL1 and RELL2 are non-canonical members of TNFR family that may be distinct GM130 and Striatin may regulate GCK-III phosphorylation and from those of classical members in terms of signaling. The C-terminal cellular localization domain of SPAK/OSR1 may bind to the ‘RFRV’ motif found in the GM130 is a Golgi matrix protein largely consisting of coiled-coil cytoplasmic domain of receptor expressed in lymphoid tissue subfamily domains, which functions to maintain the structural integrity of members, leading to phosphorylation of receptor expressed in lymphoid Golgi.91–93 The very C-terminus of GM130 may bind to and stimulate tissue and downstream signaling.109,110 Interestingly, the activity of SPAK the catalytic activity of HtrA1, a serine protease that inhibits TGF-b signa- can be downregulated by the TNF family member TRAIL, indicating a ling.94 EspG proteins produced by enteric pathogens may interact with potential role in immune regulation.111 GM130 and disrupt protein secretion of the host cells.95 GCK-III kinases OSR1 has recently been identified as a key regulator of ion home- may target the Golgi apparatusthroughbindingwithGM130 ostasis and cell volume downstream of the WNK signaling path- (Figure 3).53,96 Despite forming a stable complex, PDCD10 and way.112–116 OSR1 and SPAK target the Na–K–Cl cotransporter. Striatin may differentially regulate GCK-III. For example, PDCD10 MO25 is a potent regulator of OSR1 kinase activity.76 In addition, knockdown promotes Golgi localization of MST4 in HeLa cells. On we have found that OSR1 is self-inhibited and MO25 association with the contrary, knockdown of Striatin impaired MST4 localization to OSR1 is dependent on site-specific phosphorylation of OSR1. Golgi. Given that Striatin is a component of the protein phosphatase 2 Moreover, the kinase activity of OSR1 is subject to differential regu- holo enzyme, it is likely that high levels of Striatin would decrease the lation of cations including Mg21 and Mn21 (unpublished data). OSR1 phosphorylation level of MST4, leading to inactive conformation. may regulate T-cell activation through control of osmotic pressure. As mentioned, PDCD10 has been reported to enhance the activa- Therefore, it would be intriguing to correlate the kinase activity of tion of MST4.78,81 We therefore hypothesize that the Golgi matrix OSR1 to ion homeostasis and T-cell activation.

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Our preliminary studies suggest that the regulatory mechanism of 3 Hu MC, Wang Y, Qiu WR, Mikhail A, Meyer CF, Tan TH. Hematopoietic progenitor kinase-1 (HPK1) stress response signaling pathway activates IkappaB kinases (IKK- GCK-VI activation is likely a coordinated process between MO25 and alpha/beta) and IKK-beta is a developmentally regulated protein kinase. Oncogene other yet-to-be identified factors. To date, fragments of the kinase 1999; 18: 5514–5524. domain and the C-terminal domain of OSR1 have been structurally 4 Brenner D, Brechmann M, Rohling S, Tapernoux M, Mock T, Winter D et al. 117–119 Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells. characterized. However, the overall full-length structures of Proc Natl Acad Sci USA 2009; 106: 14508–14513. GCK-VI, as well as the structures of their complexes with MO25, are still 5 Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP et al. The kinase GLK controls not available. Given that low-level activity has been significantly hinder- autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells. Nat Immunol 2012; 12: 1113–1118. ing the functional study of GCK-VI, combined biochemical and struc- 6 Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH. Human HPK1, a novel human tural studies that dissect the kinase activation mechanism are necessary to hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. facilitate further functional investigation of GCK-VI in T-cell activation. Genes Dev 1996; 10: 2251–2264. 7 Arnold R, Liou J, Drexler HC, Weiss A, Kiefer F. Caspase-mediated cleavage of hematopoietic progenitor kinase 1 (HPK1) converts an activator of NFkappaB into OTHER GCKS RELEVANT TO IMMUNE REGULATION an inhibitor of NFkappaB. J Biol Chem 2001; 276: 14675–14684. The GCK-IV subfamily member misshapen/NIK-related kinase, a 8 Brenner D, Golks A, Kiefer F, Krammer PH, Arnold R. Activation or suppression of 98 NFkappaB by HPK1 determines sensitivity to activation-induced cell death. EMBO J novel component of the STRIPAK complex, is highly expressed in 2005; 24: 4279–4290. 120 hematopoietic tissues and can activate the JNK signaling pathway. 9 Brenner D, Golks A, Becker M, Muller W, Frey CR, Novak R et al. Caspase-cleaved The expression of NIK, another GCK-IV subfamily member can be HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes. Blood 2007; 110: 3968–3977. selectively stimulated by TNF-a through a TNFR1-dependent mech- 10 Patzak IM, Konigsberger S, Suzuki A, Mak TW, Kiefer F. HPK1 competes with ADAP 121 anism. RNA interference targeting macrophage NIK protected mice for SLP-76 binding and via Rap1 negatively affects T-cell adhesion. Eur J Immunol from lipopolysaccharide-induced lethality by preventing TNF-a and 2010; 40: 3220–3225. 122 11 Konigsberger S, Peckl-Schmid D, Zaborsky N, Patzak I, Kiefer F, Achatz G. HPK1 IL-1b secretion. The GCK-V subfamily member LOK is a 130-kDa associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte serine/threonine kinase predominantly expressed in lymphoid adhesion. PLoS ONE 2010; 5: e12468. tissues.123 LOK does not activate MAPK signaling but is involved in 12 Katagiri K, Imamura M, Kinashi T. Spatiotemporal regulation of the kinase Mst1 by 124 binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol LFA-1-mediated lymphocyte adhesion. SLK, which is similar to 2006; 7: 919–928. LOK, can regulate focal adhesion turnover through unknown mech- 13 Katz P, Whalen G, Kehrl JH. Differential expression of a novel protein kinase in human anism that involves FAK.125–127 B lymphocytes. Preferential localization in the germinal center. J Biol Chem 1994; 269: 16802–16809. The GCK-VIII subfamily member TAO2 is a mitogen-activated 14 Zhong J, Gavrilescu LC, Molnar A, Murray L, Garafalo S, Kehrl JH et al. GCK is essential protein kinase kinase kinase which associates with and activates to systemic inflammation and pattern recognition receptor signaling to JNK and p38. MAPK/extracellular signal-regulated kinase kinase 3 (MEK3) and Proc Natl Acad Sci USA 2009; 106: 4372–4377. 128 15 Huang J, Wu S, Barrera J, Matthews K, Pan D. The Hippo signaling pathway MEK6 to activate p38. Since p38 regulates the expression of inflam- coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the matory cytokines, TAO2 may be considered for therapeutic targeting Drosophila Homolog of YAP. Cell 2005; 122: 421–434. for diseases such as autoimmunity. For example, TAO2 can associate 16 Liu AM, Wong KF, Jiang X, Qiao Y, Luk JM. Regulators of mammalian Hippo pathway in cancer. Biochim Biophys Acta 2012; 1826: 357–364. with TGF-b activated kinase 1 (TAK1) to inhibit TAK1-mediated 17 Hwang E, Ryu KS, Paakkonen K, Guntert P, Cheong HK, Lim DS et al. Structural 129 activation of NF-kB. TAO2 may regulate TAK1 function through insight into dimeric interaction of the SARAH domains from Mst1 and RASSF interfering with the interaction between TAK1 and IkappaB kinase. family proteins in the apoptosis pathway. Proc Natl Acad Sci USA 2007; 104: 9236–9241. Furthermore, TAO2 does not inhibit the activation of JNK by TAK1, 18 Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. Regulation of the MST1 kinase by suggesting that TAO2 regulation of TAK1 is important to activate autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by specific intracellular signaling pathways. Ras. Biochem J 2004; 381: 453–462. 19 Graves JD, Gotoh Y, Draves KE, Ambrose D, Han DK, Wright M et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. PERSPECTIVE EMBO J 1998; 17: 2224–2234. 20 Graves JD, Draves KE, Gotoh Y, Krebs EG, Clark EA. 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