Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Germinal center kinases in immune regulation

Abstract

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.

Introduction

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.

Figure 1
figure1

GCKs in immune regulation. GCK, germinal center kinase.

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.

Figure 2
figure2

GCK-II signaling network. DAXX, death-associated protein 6; GCK, germinal center kinase; MAPK, mitogen-activated protein kinase; PP2A, protein phosphatase 2; PRX-1, peroxiredoxin 1; Rap1, Ras-related protein 1; RapL, regulator for cell adhesion and polarization enriched in lymphoid tissues.

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 CD4CD8+ 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

Figure 3
figure3

GCK-III and its regulators. ERM, ezrin–radixin–moesin; FAK, focal adhesion kinase; GCK, germinal center kinase; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; PDCD10, programmed cell death 10; PP2A, protein phosphatase 2.

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.

Perspective

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.

References

  1. 1

    Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001; 22: 153–183.

    CAS  PubMed  Google Scholar 

  2. 2

    Boomer JS, Tan TH . Functional interactions of HPK1 with adaptor proteins. J Cell Biochem 2005; 95: 34–44.

    CAS  PubMed  Google Scholar 

  3. 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-alpha/beta) and IKK-beta is a developmentally regulated protein kinase. Oncogene 1999; 18: 5514–5524.

    CAS  PubMed  Google Scholar 

  4. 4

    Brenner D, Brechmann M, Rohling S, Tapernoux M, Mock T, Winter D et al. Phosphorylation of CARMA1 by HPK1 is critical for NF-kappaB activation in T cells. Proc Natl Acad Sci USA 2009; 106: 14508–14513.

    CAS  PubMed  Google Scholar 

  5. 5

    Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP et al. The kinase GLK controls autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells. Nat Immunol 2012; 12: 1113–1118.

    Google Scholar 

  6. 6

    Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH . Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev 1996; 10: 2251–2264.

    CAS  PubMed  Google Scholar 

  7. 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 an inhibitor of NFkappaB. J Biol Chem 2001; 276: 14675–14684.

    CAS  PubMed  Google Scholar 

  8. 8

    Brenner D, Golks A, Kiefer F, Krammer PH, Arnold R . Activation or suppression of NFkappaB by HPK1 determines sensitivity to activation-induced cell death. EMBO J 2005; 24: 4279–4290.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Brenner D, Golks A, Becker M, Muller W, Frey CR, Novak R et al. Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes. Blood 2007; 110: 3968–3977.

    CAS  PubMed  Google Scholar 

  10. 10

    Patzak IM, Konigsberger S, Suzuki A, Mak TW, Kiefer F . HPK1 competes with ADAP for SLP-76 binding and via Rap1 negatively affects T-cell adhesion. Eur J Immunol 2010; 40: 3220–3225.

    CAS  PubMed  Google Scholar 

  11. 11

    Konigsberger S, Peckl-Schmid D, Zaborsky N, Patzak I, Kiefer F, Achatz G . HPK1 associates with SKAP-HOM to negatively regulate Rap1-mediated B-lymphocyte adhesion. PLoS ONE 2010; 5: e12468.

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Katagiri K, Imamura M, Kinashi T . Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol 2006; 7: 919–928.

    CAS  PubMed  Google Scholar 

  13. 13

    Katz P, Whalen G, Kehrl JH . Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center. J Biol Chem 1994; 269: 16802–16809.

    CAS  PubMed  Google Scholar 

  14. 14

    Zhong J, Gavrilescu LC, Molnar A, Murray L, Garafalo S, Kehrl JH et al. GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38. Proc Natl Acad Sci USA 2009; 106: 4372–4377.

    CAS  PubMed  Google Scholar 

  15. 15

    Huang J, Wu S, Barrera J, Matthews K, Pan D . The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Cell 2005; 122: 421–434.

    CAS  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. 17

    Hwang E, Ryu KS, Paakkonen K, Guntert P, Cheong HK, Lim DS et al. Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway. Proc Natl Acad Sci USA 2007; 104: 9236–9241.

    CAS  Google Scholar 

  18. 18

    Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J . Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J 2004; 381: 453–462.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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. EMBO J 1998; 17: 2224–2234.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Graves JD, Draves KE, Gotoh Y, Krebs EG, Clark EA . Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis. J Biol Chem 2001; 276: 14909–14915.

    CAS  PubMed  Google Scholar 

  21. 21

    Glantschnig H, Rodan GA, Reszka AA . Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. J Biol Chem 2002; 277: 42987–42996.

    CAS  PubMed  Google Scholar 

  22. 22

    Lee KK, Ohyama T, Yajima N, Tsubuki S, Yonehara S . MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem 2001; 276: 19276–19285.

    CAS  PubMed  Google Scholar 

  23. 23

    Song JJ, Lee YJ . Differential cleavage of Mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily. Cell Signal 2008; 20: 892–906.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Mou F, Praskova M, Xia F, van Buren D, Hock H, Avruch J et al. The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J Exp Med 2012; 209: 741–759.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Cinar B, Fang PK, Lutchman M, Di Vizio D, Adam RM, Pavlova N et al. The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1. EMBO J 2007; 26: 4523–4534.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Zhou D, Medoff BD, Chen L, Li L, Zhang XF, Praskova M et al. The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naive T cells. Proc Natl Acad Sci USA 2008; 105: 20321–20326.

    CAS  PubMed  Google Scholar 

  27. 27

    Choi J, Oh S, Lee D, Oh HJ, Park JY, Lee SB et al. Mst1-FoxO signaling protects Naive T lymphocytes from cellular oxidative stress in mice. PLoS ONE 2009; 4: e8011.

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Nehme NT, Pachlopnik Schmid J, Debeurme F, Andre-Schmutz I, Lim A, Nitschke P et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T cells survival. Blood 2012; 119: 3458–3468.

    CAS  Google Scholar 

  29. 29

    Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schaffer AA et al. The phenotype of human STK4 deficiency. Blood 2012; 119: 3450–3457.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Dong Y, Du X, Ye J, Han M, Xu T, Zhuang Y et al. A cell-intrinsic role for Mst1 in regulating thymocyte egress. J Immunol 2009; 183: 3865–3872.

    CAS  PubMed  Google Scholar 

  31. 31

    Kliche S, Worbs T, Wang X, Degen J, Patzak I, Meineke B et al. CCR7-mediated LFA-1 functions in T cells are regulated by 2 independent ADAP/SKAP55 modules. Blood 2012; 119: 777–785.

    CAS  PubMed  Google Scholar 

  32. 32

    Katagiri K, Katakai T, Ebisuno Y, Ueda Y, Okada T, Kinashi T . Mst1 controls lymphocyte trafficking and interstitial motility within lymph nodes. EMBO J 2009; 28: 1319–1331.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Perlman R, Schiemann WP, Brooks MW, Lodish HF, Weinberg RA . TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat Cell Biol 2001; 3: 708–714.

    CAS  PubMed  Google Scholar 

  34. 34

    Leal-Sanchez J, Couzinet A, Rossin A, Abdel-Sater F, Chakrabandhu K, Luci C et al. Requirement for Daxx in mature T-cell proliferation and activation. Cell Death Differ 2007; 14: 795–806.

    CAS  PubMed  Google Scholar 

  35. 35

    Huang L, Xu GL, Zhang JQ, Tian L, Xue JL, Chen JZ et al. Daxx interacts with HIV-1 integrase and inhibits lentiviral gene expression. Biochem Biophys Res Commun 2008; 373: 241–245.

    CAS  PubMed  Google Scholar 

  36. 36

    Hwang J, Kalejta RF . Human cytomegalovirus protein pp71 induces Daxx SUMOylation. J Virol 2009; 83: 6591–6598.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Netsawang J, Noisakran S, Puttikhunt C, Kasinrerk W, Wongwiwat W, Malasit P et al. Nuclear localization of dengue virus capsid protein is required for DAXX interaction and apoptosis. Virus Res 2010; 147: 275–283.

    CAS  PubMed  Google Scholar 

  38. 38

    Schreiner S, Wimmer P, Sirma H, Everett RD, Blanchette P, Groitl P et al. Proteasome-dependent degradation of Daxx by the viral E1B-55K protein in human adenovirus-infected cells. J Virol 2010; 84: 7029–7038.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Drane P, Ouararhni K, Depaux A, Shuaib M, Hamiche A . The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev 2010; 24: 1253–1265.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Schreiner S, Wimmer P, Groitl P, Chen SY, Blanchette P, Branton PE et al. Adenovirus type 5 early region 1B 55K oncoprotein-dependent degradation of cellular factor Daxx is required for efficient transformation of primary rodent cells. J Virol 2011; 85: 8752–8765.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Hwang J, Kalejta RF . In vivo analysis of protein sumoylation induced by a viral protein: Detection of HCMV pp71-induced Daxx sumoylation. Methods 2011; 55: 160–165.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Tsai K, Thikmyanova N, Wojcechowskyj JA, Delecluse HJ, Lieberman PM . EBV tegument protein BNRF1 disrupts DAXX–ATRX to activate viral early gene transcription. PLoS Pathog 2011; 7: e1002376.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Khunchai S, Junking M, Suttitheptumrong A, Yasamut U, Sawasdee N, Netsawang J et al. Interaction of dengue virus nonstructural protein 5 with Daxx modulates RANTES production. Biochem Biophys Res Commun 2012; 423: 398–403.

    CAS  PubMed  Google Scholar 

  44. 44

    Yun HJ, Yoon JH, Lee JK, Noh KT, Yoon KW, Oh SP et al. Daxx mediates activation-induced cell death in microglia by triggering MST1 signalling. EMBO J 2011; 30: 2465–2476.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Giovinazzi S, Lindsay CR, Morozov VM, Escobar-Cabrera E, Summers MK, Han HS et al. Regulation of mitosis and taxane response by Daxx and Rassf1. Oncogene 2012; 31: 13–26.

    CAS  PubMed  Google Scholar 

  46. 46

    Liu F, Du ZY, He JL, Liu XQ, Yu QB, Wang YX . FTH1 binds to Daxx and inhibits Daxx-mediated cell apoptosis. Mol Biol Rep 2012; 39: 873–879.

    CAS  PubMed  Google Scholar 

  47. 47

    Ishii T, Warabi E, Yanagawa T . Novel roles of peroxiredoxins in inflammation, cancer and innate immunity. J Clin Biochem Nutr 2012; 50: 91–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Morinaka A, Funato Y, Uesugi K, Miki H . Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis. Oncogene 2011; 30: 4208–4218.

    CAS  PubMed  Google Scholar 

  49. 49

    Lee W, Choi KS, Riddell J, Ip C, Ghosh D, Park JH et al. Human peroxiredoxin 1 and 2 are not duplicate proteins: the unique presence of CYS83 in Prx1 underscores the structural and functional differences between Prx1 and Prx2. J Biol Chem 2007; 282: 22011–22022.

    CAS  PubMed  Google Scholar 

  50. 50

    Matsumura T, Okamoto K, Iwahara S, Hori H, Takahashi Y, Nishino T et al. Dimer-oligomer interconversion of wild-type and mutant rat 2-Cys peroxiredoxin: disulfide formation at dimer–dimer interfaces is not essential for decamerization. J Biol Chem 2008; 283: 284–293.

    CAS  PubMed  Google Scholar 

  51. 51

    Jin Y, Dong L, Lu Y, Wu W, Hao Q, Zhou Z et al. Dimerization and cytoplasmic localization regulate Hippo kinase signaling activity in organ size control. J Biol Chem 2012; 287: 5784–5796.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Huang CY, Wu YM, Hsu CY, Lee WS, Lai MD, Lu TJ et al. Caspase activation of mammalian sterile 20-like kinase 3 (Mst3). Nuclear translocation and induction of apoptosis. J Biol Chem 2002; 277: 34367–34374.

    CAS  PubMed  Google Scholar 

  53. 53

    Preisinger C, Short B, de Corte V, Bruyneel E, Haas A, Kopajtich R et al. YSK1 is activated by the Golgi matrix protein GM130 and plays a role in cell migration through its substrate 14–3–3zeta. J Cell Biol 2004; 164: 1009–1020.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Zhang H, Ma X, Deng X, Chen Y, Mo X, Zhang Y et al. PDCD10 interacts with STK25 to accelerate cell apoptosis under oxidative stress. Front Biosci 2012; 17: 2295–2305.

    Google Scholar 

  55. 55

    Matsuki T, Matthews RT, Cooper JA, van der Brug MP, Cookson MR, Hardy JA et al. Reelin and stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment. Cell 2010; 143: 826–836.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Qian Z, Lin C, Espinosa R, LeBeau M, Rosner MR . Cloning and characterization of MST4, a novel Ste20-like kinase. J Biol Chem 2001; 276: 22439–22445.

    CAS  PubMed  Google Scholar 

  57. 57

    Lin JL, Chen HC, Fang HI, Robinson D, Kung HJ, Shih HM . MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 2001; 20: 6559–6569.

    CAS  PubMed  Google Scholar 

  58. 58

    Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM . Structure of the LKB1–STRAD–MO25 complex reveals an allosteric mechanism of kinase activation. Science 2009; 326: 1707–1711.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    ten Klooster JP, Jansen M, Yuan J, Oorschot V, Begthel H, Di Giacomo V et al. Mst4 and Ezrin induce brush borders downstream of the Lkb1/Strad/Mo25 polarization complex. Dev Cell 2009; 16: 551–562.

    CAS  PubMed  Google Scholar 

  60. 60

    Milburn CC, Boudeau J, Deak M, Alessi DR, van Aalten DM . Crystal structure of MO25 alpha in complex with the C terminus of the pseudo kinase STE20-related adaptor. Nat Struct Mol Biol 2004; 11: 193–200.

    CAS  PubMed  Google Scholar 

  61. 61

    Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D et al. Analysis of the LKB1–STRAD–MO25 complex. J Cell Sci 2004; 117: 6365–6375.

    CAS  PubMed  Google Scholar 

  62. 62

    Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003; 2: 28.

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Bignell GR, Barfoot R, Seal S, Collins N, Warren W, Stratton MR . Low frequency of somatic mutations in the LKB1/Peutz–Jeghers syndrome gene in sporadic breast cancer. Cancer Res 1998; 58: 1384–1386.

    CAS  PubMed  Google Scholar 

  64. 64

    Contreras CM, Akbay EA, Gallardo TD, Haynie JM, Sharma S, Tagao O et al. Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. Dis Model Mech 2010; 3: 181–193.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Han S, Khuri FR, Roman J . Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. Cancer Res 2006; 66: 315–323.

    CAS  PubMed  Google Scholar 

  66. 66

    Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 2002; 62: 3659–3662.

    CAS  PubMed  Google Scholar 

  67. 67

    Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ et al. STK11/LKB1 Peutz–Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001; 159: 2017–2022.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA et al. Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz–Jeghers syndrome. Oncogene 2000; 19: 164–168.

    CAS  PubMed  Google Scholar 

  69. 69

    Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007; 448: 807–810.

    CAS  PubMed  Google Scholar 

  70. 70

    Matsumoto S, Iwakawa R, Takahashi K, Kohno T, Nakanishi Y, Matsuno Y et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene 2007; 26: 5911–5918.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Resta N, Simone C, Mareni C, Montera M, Gentile M, Susca F et al. STK11 mutations in Peutz–Jeghers syndrome and sporadic colon cancer. Cancer Res 1998; 58: 4799–4801.

    CAS  PubMed  Google Scholar 

  72. 72

    Sherman MH, Kuraishy AI, Deshpande C, Hong JS, Cacalano NA, Gatti RA et al. AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Mol Cell 2010; 39: 873–885.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Cao Y, Li H, Liu H, Zhang M, Hua Z, Ji H et al. LKB1 regulates TCR-mediated PLCgamma1 activation and thymocyte positive selection. EMBO J 2011; 30: 2083–2093.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Cao Y, Li H, Liu H, Zheng C, Ji H, Liu X . The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression. Cell Res 2010; 20: 99–108.

    CAS  Google Scholar 

  75. 75

    Moser TS, Schieffer D, Cherry S . AMP-activated kinase restricts rift valley fever virus infection by inhibiting fatty acid synthesis. PLoS Pathog 2012; 8: e1002661.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Filippi BM, de los Heros P, Mehellou Y, Navratilova I, Gourlay R, Deak M et al. MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 protein kinases. EMBO J 2011; 30: 1730–1741.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Fidalgo M, Fraile M, Pires A, Force T, Pombo C, Zalvide J . CCM3/PDCD10 stabilizes GCKIII proteins to promote Golgi assembly and cell orientation. J Cell Sci 2010; 123: 1274–1284.

    CAS  PubMed  Google Scholar 

  78. 78

    Ma X, Zhao H, Shan J, Long F, Chen Y, Zhang Y et al. PDCD10 interacts with Ste20-related kinase MST4 to promote cell growth and transformation via modulation of the ERK pathway. Mol Biol Cell 2007; 18: 1965–1978.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Li X, Zhang R, Zhang H, He Y, Ji W, Min W et al. Crystal structure of CCM3, a cerebral cavernous malformation protein critical for vascular integrity. J Biol Chem 2010; 285: 24099–24107.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Lauenborg B, Kopp K, Krejsgaard T, Eriksen KW, Geisler C, Dabelsteen S et al. Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis. APMIS 2010; 118: 719–728.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Ceccarelli DF, Laister RC, Mulligan VK, Kean MJ, Goudreault M, Scott IC et al. CCM3/PDCD10 heterodimerizes with germinal center kinase III (GCKIII) proteins using a mechanism analogous to CCM3 homodimerization. J Biol Chem 2011; 286: 25056–25064.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Kean MJ, Ceccarelli DF, Goudreault M, Sanches M, Tate S, Larsen B et al. Structure–function analysis of core STRIPAK proteins: a signaling complex implicated in Golgi polarization. J Biol Chem 2011; 286: 25065–25075.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Sanchez-Gonzalez P, Jellali K, Villalobo A . Calmodulin-mediated regulation of the epidermal growth factor receptor. FEBS J 2010; 277: 327–342.

    CAS  PubMed  Google Scholar 

  84. 84

    Skelding KA, Rostas JA, Verrills NM . Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II. Cell Cycle 2011; 10: 631–639.

    CAS  PubMed  Google Scholar 

  85. 85

    Grabarek Z . Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins. Biochim Biophys Acta 2011; 1813: 913–921.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Bozym RA, Delorme-Axford E, Harris K, Morosky S, Ikizler M, Dermody TS et al. Focal adhesion kinase is a component of antiviral RIG-I-like receptor signaling. Cell Host Microbe 2012; 11: 153–166.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Semaan N, Alsaleh G, Gottenberg JE, Wachsmann D, Sibilia J . Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J Immunol 2008; 180: 3485–3491.

    CAS  PubMed  Google Scholar 

  88. 88

    Garron ML, Arthos J, Guichou JF, McNally J, Cicala C, Arold ST . Structural basis for the interaction between focal adhesion kinase and CD4. J Mol Biol 2008; 375: 1320–1328.

    CAS  PubMed  Google Scholar 

  89. 89

    Schaller MD . Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci 2010; 123: 1007–1013.

    CAS  PubMed  Google Scholar 

  90. 90

    Hall JE, Fu W, Schaller MD . Focal adhesion kinase: exploring Fak structure to gain insight into function. Int Rev Cell Mol Biol 2011; 288: 185–225.

    CAS  PubMed  Google Scholar 

  91. 91

    Lowe M, Rabouille C, Nakamura N, Watson R, Jackman M, Jamsa E et al. Cdc2 kinase directly phosphorylates the cis-Golgi matrix protein GM130 and is required for Golgi fragmentation in mitosis. Cell 1998; 94: 783–793.

    CAS  PubMed  Google Scholar 

  92. 92

    Nakamura N, Lowe M, Levine TP, Rabouille C, Warren G . The vesicle docking protein p115 binds GM130, a cis-Golgi matrix protein, in a mitotically regulated manner. Cell 1997; 89: 445–455.

    CAS  PubMed  Google Scholar 

  93. 93

    Nakamura N, Rabouille C, Watson R, Nilsson T, Hui N, Slusarewicz P et al. Characterization of a cis-Golgi matrix protein, GM130. J Cell Biol 1995; 131: 1715–1726.

    CAS  PubMed  Google Scholar 

  94. 94

    Murwantoko, Yano M, Ueta Y, Murasaki A, Kanda H, Oka C et al. Binding of proteins to the PDZ domain regulates proteolytic activity of HtrA1 serine protease. Biochem J 2004; 381: 895–904.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Clements A, Smollett K, Lee SF, Hartland EL, Lowe M, Frankel G . EspG of enteropathogenic and enterohemorrhagic E. coli binds the Golgi matrix protein GM130 and disrupts the Golgi structure and function. Cell Microbiol 2011; 13: 1429–1439.

    CAS  PubMed  Google Scholar 

  96. 96

    Fuller SJ, McGuffin LJ, Marshall AK, Giraldo A, Pikkarainen S, Clerk A et al. A novel non-canonical mechanism of regulation of MST3 (mammalian Sterile20-related kinase 3). Biochem J 2012; 442: 595–610.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Ribeiro PS, Josue F, Wepf A, Wehr MC, Rinner O, Kelly G et al. Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling. Mol Cell 2010; 39: 521–534.

    CAS  PubMed  Google Scholar 

  98. 98

    Hyodo T, Ito S, Hasegawa H, Asano E, Maeda M, Urano T et al. Misshapen-like kinase 1 (MINK1) is a novel component of striatin interacting phosphatase and kinase (STRIPAK) and is required for the completion of cytokinesis. J Biol Chem 2012; 287: 25019–25029.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Fehon RG, McClatchey AI, Bretscher A . Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol 2010; 11: 276–287.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Neisch AL, Fehon RG . Ezrin, Radixin and moesin: key regulators of membrane–cortex interactions and signaling. Curr Opin Cell Biol 2011; 23: 377–382.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Arpin M, Chirivino D, Naba A, Zwaenepoel I . Emerging role for ERM proteins in cell adhesion and migration. Cell Adh Migr 2011; 5: 199–206.

    PubMed  PubMed Central  Google Scholar 

  102. 102

    Shaffer MH, Dupree RS, Zhu P, Saotome I, Schmidt RF, McClatchey AI et al. Ezrin and moesin function together to promote T cell activation. J Immunol 2009; 182: 1021–1032.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Allenspach EJ, Cullinan P, Tong J, Tang Q, Tesciuba AG, Cannon JL et al. ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity 2001; 15: 739–750.

    CAS  Google Scholar 

  104. 104

    Roumier A, Olivo-Marin JC, Arpin M, Michel F, Martin M, Mangeat P et al. The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 2001; 15: 715–728.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Lasserre R, Charrin S, Cuche C, Danckaert A, Thoulouze MI, de Chaumont F et al. Ezrin tunes T-cell activation by controlling Dlg1 and microtubule positioning at the immunological synapse. EMBO J 2010; 29: 2301–2314.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106

    Ruppelt A, Mosenden R, Gronholm M, Aandahl EM, Tobin D, Carlson CR et al. Inhibition of T cell activation by cyclic adenosine 5′-monophosphate requires lipid raft targeting of protein kinase A type I by the A-kinase anchoring protein ezrin. J Immunol 2007; 179: 5159–5168.

    CAS  PubMed  Google Scholar 

  107. 107

    Stokka AJ, Mosenden R, Ruppelt A, Lygren B, Tasken K . The adaptor protein EBP50 is important for localization of the protein kinase A–Ezrin complex in T-cells and the immunomodulating effect of cAMP. Biochem J 2010; 425: 381–388.

    CAS  Google Scholar 

  108. 108

    Li Y, Hu J, Vita R, Sun B, Tabata H, Altman A . SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. EMBO J 2004; 23: 1112–1122.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Polek TC, Talpaz M, Spivak-Kroizman T . The TNF receptor, RELT, binds SPAK and uses it to mediate p38 and JNK activation. Biochem Biophys Res Commun 2006; 343: 125–134.

    CAS  PubMed  Google Scholar 

  110. 110

    Cusick JK, Xu LG, Bin LH, Han KJ, Shu HB . Identification of RELT homologues that associate with RELT and are phosphorylated by OSR1. Biochem Biophys Res Commun 2006; 340: 535–543.

    CAS  PubMed  Google Scholar 

  111. 111

    Polek TC, Talpaz M, Spivak-Kroizman TR . TRAIL-induced cleavage and inactivation of SPAK sensitizes cells to apoptosis. Biochem Biophys Res Commun 2006; 349: 1016–1024.

    CAS  PubMed  Google Scholar 

  112. 112

    Mercier-Zuber A, O'Shaughnessy KM . Role of SPAK and OSR1 signalling in the regulation of NaCl cotransporters. Curr Opin Nephrol Hypertens 2011; 20: 534–540.

    CAS  PubMed  Google Scholar 

  113. 113

    Richardson C, Rafiqi FH, Karlsson HK, Moleleki N, Vandewalle A, Campbell DG et al. Activation of the thiazide-sensitive Na+–Cl cotransporter by the WNK-regulated kinases SPAK and OSR1. J Cell Sci 2008; 121: 675–684.

    CAS  PubMed  Google Scholar 

  114. 114

    Richardson C, Alessi DR . The regulation of salt transport and blood pressure by the WNK–SPAK/OSR1 signalling pathway. J Cell Sci 2008; 121: 3293–3304.

    CAS  PubMed  Google Scholar 

  115. 115

    Delpire E, Gagnon KB . SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. Biochem J 2008; 409: 321–331.

    CAS  PubMed  Google Scholar 

  116. 116

    Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem 2005; 280: 42685–42693.

    CAS  PubMed  Google Scholar 

  117. 117

    Lee SJ, Cobb MH, Goldsmith EJ . Crystal structure of domain-swapped STE20 OSR1 kinase domain. Protein Sci 2009; 18: 304–313.

    CAS  PubMed  Google Scholar 

  118. 118

    Villa F, Deak M, Alessi DR, van Aalten DM . Structure of the OSR1 kinase, a hypertension drug target. Proteins 2008; 73: 1082–1087.

    CAS  PubMed  Google Scholar 

  119. 119

    Villa F, Goebel J, Rafiqi FH, Deak M, Thastrup J, Alessi DR et al. Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep 2007; 8: 839–845.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Lim J, Lennard A, Sheppard PW, Kellie S . Identification of residues which regulate activity of the STE20-related kinase hMINK. Biochem Biophys Res Commun 2003; 300: 694–698.

    CAS  PubMed  Google Scholar 

  121. 121

    Tesz GJ, Guilherme A, Guntur KV, Hubbard AC, Tang X, Chawla A et al. Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNFalpha receptor 1 signaling to c-Jun and activating transcription factor 2. J Biol Chem 2007; 282: 19302–19312.

    CAS  PubMed  Google Scholar 

  122. 122

    Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E et al. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 2009; 458: 1180–1184.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Kuramochi S, Moriguchi T, Kuida K, Endo J, Semba K, Nishida E et al. LOK is a novel mouse STE20-like protein kinase that is expressed predominantly in lymphocytes. J Biol Chem 1997; 272: 22679–22684.

    CAS  PubMed  Google Scholar 

  124. 124

    Endo J, Toyama-Sorimachi N, Taya C, Kuramochi-Miyagawa S, Nagata K, Kuida K et al. Deficiency of a STE20/PAK family kinase LOK leads to the acceleration of LFA-1 clustering and cell adhesion of activated lymphocytes. FEBS Lett 2000; 468: 234–238.

    CAS  PubMed  Google Scholar 

  125. 125

    Wagner S, Storbeck CJ, Roovers K, Chaar ZY, Kolodziej P, McKay M et al. FAK/src-family dependent activation of the Ste20-like kinase SLK is required for microtubule-dependent focal adhesion turnover and cell migration. PLoS ONE 2008; 3: e1868.

    PubMed  PubMed Central  Google Scholar 

  126. 126

    Roovers K, Wagner S, Storbeck CJ, O'Reilly P, Lo V, Northey JJ et al. The Ste20-like kinase SLK is required for ErbB2-driven breast cancer cell motility. Oncogene 2009; 28: 2839–2848.

    CAS  PubMed  Google Scholar 

  127. 127

    Storbeck CJ, Wagner S, O'Reilly P, McKay M, Parks RJ, Westphal H et al. The Ldb1 and Ldb2 transcriptional cofactors interact with the Ste20-like kinase SLK and regulate cell migration. Mol Biol Cell 2009; 20: 4174–4182.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Chen Z, Cobb MH . Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2. J Biol Chem 2001; 276: 16070–16075.

    CAS  PubMed  Google Scholar 

  129. 129

    Huangfu WC, Omori E, Akira S, Matsumoto K, Ninomiya-Tsuji J . Osmotic stress activates the TAK1–JNK pathway while blocking TAK1-mediated NF-kappaB activation: TAO2 regulates TAK1 pathways. J Biol Chem 2006; 281: 28802–28810.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Zhaocai Zhou.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • germinal center kinases
  • immune regulation
  • signal transduction

Further reading

Search

Quick links