241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
299 KEGG pathways;
876 Reactome pathways;
last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Cytoplasm Cell membrane Note=Present in lipid rafts in aninactive form
Function (UniProt annotation)
Non-receptor tyrosine-protein kinase that plays anessential role in the selection and maturation of developing T-cells in the thymus and in the function of mature T-cells Plays akey role in T-cell antigen receptor (TCR)-linked signaltransduction pathways Constitutively associated with thecytoplasmic portions of the CD4 and CD8 surface receptorsAssociation of the TCR with a peptide antigen-bound MHC complexfacilitates the interaction of CD4 and CD8 with MHC class II andclass I molecules, respectively, thereby recruiting the associatedLCK protein to the vicinity of the TCR/CD3 complex LCK thenphosphorylates tyrosine residues within the immunoreceptortyrosine-based activation motifs (ITAM) of the cytoplasmic tailsof the TCR-gamma chains and CD3 subunits, initiating the TCR/CD3signaling pathway Once stimulated, the TCR recruits the tyrosinekinase ZAP70, that becomes phosphorylated and activated by LCKFollowing this, a large number of signaling molecules arerecruited, ultimately leading to lymphokine production LCK alsocontributes to signaling by other receptor molecules Associatesdirectly with the cytoplasmic tail of CD2, which leads tohyperphosphorylation and activation of LCK Also plays a role inthe IL2 receptor-linked signaling pathway that controls the T-cellproliferative response Binding of IL2 to its receptor results inincreased activity of LCK Is expressed at all stages of thymocytedevelopment and is required for the regulation of maturationevents that are governed by both pre-TCR and mature alpha betaTCR Phosphorylates other substrates including RUNX3, PTK2B/PYK2,the microtubule-associated protein MAPT, RHOH or TYROBP Interactswith FYB2 (PubMed:27335501)
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
Nuclear factor-kappa B (NF-kappa B) is the generic name of a family of transcription factors that function as dimers and regulate genes involved in immunity, inflammation and cell survival. There are several pathways leading to NF-kappa B-activation. The canonical pathway is induced by tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) or byproducts of bacterial and viral infections. This pathway relies on IKK- mediated IkappaB-alpha phosphorylation on Ser32 and 36, leading to its degradation, which allows the p50/p65 NF-kappa B dimer to enter the nucleus and activate gene transcription. Atypical pathways are IKK-independent and rely on phosphorylation of IkappaB-alpha on Tyr42 or on Ser residues in IkappaB-alpha PEST domain. The non-canonical pathway is triggered by particular members of the TNFR superfamily, such as lymphotoxin-beta (LT-beta) or BAFF. It involves NIK and IKK-alpha-mediated p100 phosphorylation and processing to p52, resulting in nuclear translocation of p52/RelB heterodimers.
The osteoclasts, multinucleared cells originating from the hematopoietic monocyte-macrophage lineage, are responsible for bone resorption. Osteoclastogenesis is mainly regulated by signaling pathways activated by RANK and immune receptors, whose ligands are expressed on the surface of osteoblasts. Signaling from RANK changes gene expression patterns through transcription factors like NFATc1 and characterizes the active osteoclast.
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit MHC class I exprssion or alter its conformation. The mechanism of NK cell killing is the same as that used by the cytotoxic T cells generated in an adaptive immune response; cytotoxic granules are released onto the surface of the bound target cell, and the effector proteins they contain penetrate the cell membrane and induce programmed cell death.
Immunity to different classes of microorganisms is orchestrated by separate lineages of effector T helper (TH)-cells, which differentiate from naive CD4+ precursor cells in response to cues provided by antigen presenting cells (APC) and include T helper type 1 (Th1) and Th2. Th1 cells are characterized by the transcription factor T-bet and signal transducer and activator of transcription (STAT) 4, and the production of IFN-gamma. These cells stimulate strong cell-mediated immune responses, particularly against intracellular pathogens. On the other hand, transcription factors like GATA-3 and STAT6 drive the generation of Th2 cells that produce IL-4, IL-5 and IL-13 and are necessary for inducing the humoral response to combat parasitic helminths (type 2 immunity) and isotype switching to IgG1 and IgE. The balance between Th1/Th2 subsets determines the susceptibility to disease states, where the improper development of Th2 cells can lead to allergy, while an overactive Th1 response can lead to autoimmunity.
Interleukin (IL)-17-producing helper T (Th17) cells serve as a subset of CD4+ T cells involved in epithelial cell- and neutrophil mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases. In vivo, Th17 differentiation requires antigen presentation and co-stimulation, and activation of antigen presenting-cells (APCs) to produce TGF-beta, IL-6, IL-1, IL-23 and IL-21. This initial activation results in the activation and up-regulation of STAT3, ROR(gamma)t and other transcriptional factors in CD4+ T cells, which bind to the promoter regions of the IL-17, IL-21 and IL-22 genes and induce IL-17, IL-21 and IL-22. In contrast, the differentiation of Th17 cells and their IL-17 expression are negatively regulated by IL-2, Th2 cytokine IL-4, IL-27 and Th1 cytokine IFN-gamma through STAT5, STAT6 and STAT1 activation, respectively. Retinoid acid and the combination of IL-2 and TGF-beta upregulate Foxp3, which also downregulates cytokines like IL-17 and IL-21. The inhibition of Th17 differentiation may serve as a protective strategy to 'fine-tune' the expression IL-17 so it does not cause excessive inflammation. Thus, balanced differentiation of Th cells is crucial for immunity and host protection.
Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells.
Human T-cell leukemia virus type 1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). It is also strongly implicated in non-neoplastic chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Expression of Tax, a viral regulatory protein is critical to the pathogenesis. Tax is a transcriptional co-factor that interfere several signaling pathways related to anti-apoptosis or cell proliferation. The modulation of the signaling by Tax involve its binding to transcription factors like CREB/ATF, NF-kappa B, SRF, and NFAT.
Primary immunodeficiencies (PIs) are a heterogeneous group of disorders, which affect cellular and humoral immunity or non-specific host defense mechanisms mediated by complement proteins, and cells such as phagocytes and natural killer (NK) cells. These disorders of the immune system cause increased susceptibility to infection, autoimmune disease, and malignancy. Most of PIs are due to genetic defects that affect cell maturation or function at different levels during hematopoiesis. Disruption of the cellular immunity is observed in patients with defects in T cells or both T and B cells. These cellular immunodeficiencies comprise 20% of all PIs. Disorders of humoral immunity affect B-cell differentiation and antibody production. They account for 70% of all PIs.
The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007
Stem cell factor (SCF) is a growth factor with membrane bound and soluble forms. It is expressed by fibroblasts and endothelial cells throughout the body, promoting proliferation, migration, survival and differentiation of hematopoetic progenitors, melanocytes and germ cells.(Linnekin 1999, Ronnstrand 2004, Lennartsson and Ronnstrand 2006). The receptor for SCF is KIT, a tyrosine kinase receptor (RTK) closely related to the receptors for platelet derived growth factor receptor, colony stimulating factor 1 (Linnekin 1999) and Flt3 (Rosnet et al. 1991). Four isoforms of c-Kit have been identified in humans. Alternative splicing results in isoforms of KIT differing in the presence or absence of four residues (GNNK) in the extracellular region. This occurs due to the use of an alternate 5' splice donor site. These GNNK+ and GNNK- variants are co-expressed in most tissues; the GNNK- form predominates and was more strongly tyrosine-phosphorylated and more rapidly internalized (Ronnstrand 2004). There are also splice variants that arise from alternative usage of splice acceptor site resulting in the presence or absence of a serine residue (Crosier et al., 1993). Finally, there is an alternative shorter transcript of KIT expressed in postmeiotic germ cells in the testis which encodes a truncated KIT consisting only of the second part of the kinase domain and thus lackig the extracellular and transmembrane domains as well as the first part of the kinase domain (Rossi et al. 1991). Binding of SCF homodimers to KIT results in KIT homodimerization followed by activation of its intrinsic tyrosine kinase activity. KIT stimulation activates a wide array of signalling pathways including MAPK, PI3K and JAK/STAT (Reber et al. 2006, Ronnstrand 2004). Defects of KIT in humans are associated with different genetic diseases and also in several types of cancers like mast cell leukaemia, germ cell tumours, certain subtypes of malignant melanoma and gastrointestinal tumours
Nef interferes with cellular signal transduction pathways in a number of ways. Nef is associated with lipid rafts through its amino-terminal myristoylation and a proline-rich SH3-binding domain. These cholesterol-rich membrane microdomains appear to concentrate potent signaling mediators. Nef was found to complex with and activate serine/threonine protein kinase PAK-2, which may contribute to activation of infected cells. In vitro, HIV-infected T cells produce enhanced levels of interleukin-2 during activation. When expressed in macrophages, Nef intersects the CD40L signaling pathway inducing secretion of chemokines and other factors that attract resting T cells and promote their infection by HIV
The presence of Nef accelerates endocytosis and lysosomal degradation of the transmembrane glycoprotein CD4. CD4 has its own internalization motif, though this motif is normally concealed by CD4 interaction with Lck, a tyrosine kinase. Nef is known to disrupt this interaction and then facilitate a cascade of protein interactions that ultimately result in the degradation of internalized CD4 protein. The final set of protein interactions that direct Nef to the beta-subunit of the COPI coatomers are at this time unclear.A benefit for the virus from CD4 down-modulation is abolition of interaction between the receptor and the Env protein of the budding virus, which likely increases HIV release from infected cell as well as infectivity of viral particles
Changes in gene expression are required for the T cell to gain full proliferative competence and to produce effector cytokines. Three transcription factors in particular have been found to play a key role in TCR-stimulated changes in gene expression, namely NF-kB, NFAT and AP-1.
A key step in NF-kB activation is the stimulation and translocation of PKC theta. The critical element that effects PKC theta activation is PI3K. This enzyme complex translocates to the plasma membrane by interacting with phospho-tyrosines on CD28 via its two SH2 domains located in p85 subunit. The p110 subunit of PI3K phosphorylates the inositol ring of PIP2 to generate PIP3 (steps 17-18). PIP3 may also be dephosphorylated by the phosphatase SHIP to generate PI-3,4-P2.
PIP3 and PI-3,4-P2 acts as binding sites to the PH domain of PKB/Akt and PDK1 (steps 19, 21 and 22). PKB is activated in response to PI3K stimulation by PDK1 (step 23). PDK1 has an essential role in regulating the activation of PKC theta and recruitment of CBM complex to the immune synapse. PKC theta is a member of novel class (DAG dependent, Ca++ independent) of PKC and the only member known to translocate to this synapse. Prior to TCR stimulation PKC theta exists in an inactive closed conformation. Upon release of DAG, it binds to PKC theta via the C1 domain and undergoes phosphorylation on tyrosine 90 by Lck to attain an open conformation. PKC theta is further phosphorylated by PDK1 on threonine 538. This step is critical for PKC activity (steps 24-26).
CARMA1 translocates to the plasma membrane following the interaction of its SH3 domain with the 'PxxP' motif on PDK1. CARMA1 is phosphorylated by PKC-theta on residue S552, leading to the oligomerization of CARMA1. This complex acts as a scaffold, recruiting Bcl10 to the synapse by interacting with their CARD domains.
Bcl10 undergoes phosphorylation mediated by the enzyme RIP2. Activated Bcl10 then mediates the ubiquitination of NEMO by recruiting MALT1 and TRAF6. MALT1 binds to Bcl10 with its Ig-like domains and undergoes oligomerization. TRAF6 binds to the oligomerized MALT1 and also undergoes oligomerization.
Oligomerized TRAF6 acts as a ubiquitin-protein ligase, catalyzing auto-K63-linked polyubiquitination (steps 27-33). This K-63 ubiquitinated TRAF6 activates TAK1 kinase bound to TAB2 and also ubiquitinates NEMO/IKK-gamma in the IKK complex. TAK1 undergoes autophosphorylation on residues T184 and T187 and gets activated. Activated TAK1 kinase phosphorylates IKK-beta on residues S177 and S181 in the activation loop and activates the IKK kinase activity. IKK-beta phosphorylates the IkB-alpha bound to the NF-kB heterodimer, on residues S19 and S23 and directs IkB-beta to 26S proteasome degradation (step 34-38 & 40).
The NF-kB heterodimer with a free NTS sequence finally migrates to the nucleus to regulate gene transcription (step 39)
Prior to T cell receptor (TCR) stimulation, CD4/CD8 associated Lck remains seperated from the TCR and is maintained in an inactive state by the action of Csk. Csk phosphorylates the negative regulatory tyrosine of Lck and inactivates the Lck kinase domain.
Upon TCR stimulation, CD4/CD8 associated Lck co-localizes with the TCR leading to the phosphorylation of the CD3 and TCR subunit. Lck becomes activated by way of CD45-mediated dephosphorylation of negative regulatory tyrosine residues. The presence to PAG-bound Csk is further reduced via the dephosphorylation of PAG (step 1).
Lck is further activated by trans-autophosphorylation on the tyrosine residue on its activation loop (step 2). Active Lck further phosphorylates the tyrosine residues on CD3 chains. The signal-transducing CD3 delta/epsilon/gamma and TCR zeta chains contain a critical signaling motif known as the immunoreceptor tyrosine-based activation motif (ITAM). The two critical tyrosines of each ITAM motif are phosphorylated by Lck (step 3)
The dual phosphorylated ITAMs recruit Syk kinase ZAP-70 via their tandem SH2 domains (step 4). ZAP-70 subsequently undergoes phosphorylation on multiple tyrosine residues for further activation. ZAP-70 includes both positive and negative regulatory sites. Tyrosine 493 is a conserved regulatory site found within the activation loop of the kinase domain. This site has shown to be a positive regulatory site required for ZAP-70 kinase activity and is phosphorylated by Lck (step 5). This phosphorylation contributes to the active conformation of the catalytic domain. Later ZAP-70 undergoes trans-autophosphorylation at Y315 and Y319 (step 6). These sites appear to be positive regulatory sites. ZAP-70 achieves its full activation after the trans-autophosphorylation. Activated ZAP-70 along with Lck phosphorylates the multiple tyrosine residues in the adaptor protein LAT (step 7)
In addition to serving as a scaffold via auto-phosphorylation, ZAP-70 also phosphorylates a restricted set of substrates following TCR stimulation - including LAT and SLP-76. These substrates have been recognized to play pivotal role in TCR signaling by releasing second messengers. When phosphorylated, LAT and SLP-76 act as adaptor proteins which serve as nucleation points for the construction of a higher order signalosome: GADS, PLC-gamma1 and GRB2 bind to the LAT on the phosphorylated tyrosine residues (steps 8 and 13). SLP-76 and SOS are then moved to the signalosome by interacting with the SH3 domains of GRB2 and GADS via their proline rich sequences (step 9). Three SLP-76 acidic domain N-term tyrosine residues are phosphorylated by ZAP-70, once SLP-76 binds to GADS (step 10). These phospho-tyrosine residues act as binding sites to the SH2 domains of PLC-gamma1, Vav and Itk (steps 11 and 12).
PLC-gamma1 is activated by dual phosphorylation on the tyrosine residues at positions 771, 783 and 1254 by Itk and ZAP-70 (step 14). Phosphorylated PLC-gamma1 subsequently detaches from LAT and SLP-76 and translocates to the plasma membrane by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) via its PH domain (step 15). PLC-gamma1 goes on to hydrolyse PIP2 to second messengers DAG and IP3. These second messengers are involved in PKC and NF-kB activation and calcium mobilization (step 16)
PECAM-1/CD31 is a member of the immunoglobulin superfamily (IgSF) and has been implicated to mediate the adhesion and trans-endothelial migration of T-lymphocytes into the vascular wall, T cell activation and angiogenesis. It has six Ig homology domains within its extracellularly and an ITIM motif within its cytoplasmic region. PECAM-1 mediates cellular interactions by both homophilic and heterophilic interactions. The cytoplasmic domain of PECAM-1 contains tyrosine residues which serves as docking sites for recruitment of cytosolic signaling molecules. Under conditions of platelet activation, PECAM-1 is phosphorylated by Src kinase members. The tyrosine residues 663 and 686 are required for recruitment of the SH2 domain containing PTPs
Signaling by PI3K/AKT is frequently constitutively activated in cancer via gain-of-function mutations in one of the two PI3K subunits - PI3KCA (encoding the catalytic subunit p110alpha) or PIK3R1 (encoding the regulatory subunit p85alpha). Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011)
In response to receptor ligation, the tyrosine residues in DAP12's immunoreceptor tyrosine-based activation motif (ITAM) are phosphorylated by Src family kinases. These phosphotyrosines form the docking site for the protein tyrosine kinase SYK in myeloid cells and SYK and ZAP70 in NK cells. DAP12-bound SYK autophosphorylates and phosphorylates the scaffolding molecule LAT, recruiting the proximal signaling molecules phosphatidylinositol-3-OH kinase (PI3K), phospholipase-C gamma (PLC-gamma), GADS (GRB2-related adapter downstream of SHC), SLP76 (SH2 domain-containing leukocyte protein of 76 kDa), GRB2:SOS (Growth factor receptor-bound protein 2:Son of sevenless homolog 1) and VAV. All of these intermediate signalling molecules result in the recruitment and activation of kinases AKT, CBL (Casitas B-lineage lymphoma) and ERK (extracellular signal-regulated kinase), and rearrangement of the actin cytoskeleton (actin polymerization) finally leading to cellular activation. PLC-gamma generates the secondary messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3), leading to activation of protein kinase C (PKC) and calcium mobilization, respectively (Turnbull & Colonna 2007, Klesney-Tait et al. 2006)
In naive T cells, CD28 costimulation enhances cell cycle entry, potently stimulates expression of both the mitogenic lymphokine interleukin-2 (IL-2) and its receptor, and stimulates the activation of an antiapoptotic program. CD28 engages with one or both members of the B7 receptor family, B7.1 and B7.2. Upon ligand binding the tyrosines and proline-rich motifs present in the cytoplasmic tail of CD28 are phosphorylated by Lck or Fyn. Upon phosphorylation CD28 recruits and induces phosphorylation and activation of a more restricted set of intracellular signaling components that, together with those mobilized by the TCR, contribute to convert membrane-based biochemical and biophysical changes into gene activation events. Proteins like PI3K, Vav-1, Tec and Itk kinases, AKT, and the Dok-1 adaptor have been identified as elements of the CD28 signaling pathway by biochemical or genetic approaches or both
PI3Ks can be activated by a number of different receptors, including the TcR (T cell receptor), co-stimulatory receptors (CD28), cytokine receptors and chemokine receptors. However, the specific roles of PI3Ks downstream of these receptors vary. CD28 contains the YMNM consensus PI3K-binding motif, and PI3K recruitment by CD28 contributes to or complements TCR-dependent PI3K signaling. Activation of PI3K promotes PIP3 production at the plasma membrane and several potential target molecules for this phospholipid have been implicated in PI3K pathways downstream of the TcR and CD28. Of these targets, at least Vav and Akt have been implicated in CD28 costimulation of T cell activation. AKT/PKB connects PI3K to signaling pathways that promote cytokine transcription, survival, cell-cycle entry and growth
CD28 binds to several intracellular proteins including PI3 kinase, Grb-2, Gads and ITK. Grb-2 specifically co-operates with Vav-1 in the up-regulation of NFAT/AP-1 transcription. CD28 costimulation resulted in a prolonged and sustained phosphorylation and membrane localization of Vav1 in comparison to T-cell receptor activation alone. Tyrosine-phosphorylated Vav1 is an early point of integration between the signaling routes triggered by the T-cell receptor and CD28.Vav1 transduces TCR and co-stimulatory signals to multiple biochemical pathways and several cytoskeleton-dependent processes. The products of Vav1 activation, Rac1 and Cdc42, in turn activate the mitogen-activated protein kinases JNK and p38. Vav1 is also required for TCR-induced calcium flux, activation of the ERK MAP kinase pathway, activation of the NF-kB transcription factor, inside-out activation of the integrin LFA-1, TCR clustering, and polarisation of the T cell
CTLA4 is one of the best studied inhibitory receptors of the CD28 superfamily. CTLA4 inhibits Tcell activation by reducing IL2 production and IL2 expression, and by arresting T cells at the G1 phase of the cell cycle. CTLA-4 expressed by a T cell subpopulation exerts a dominant control on the proliferation of other T cells, which limits autoreactivity. CTLA4 also blocks CD28 signals by competing for the ligands B71 and B72 in the limited space between T cells and antigenpresenting cells. Though the mechanism is obscure, CTLA4 may also propagate inhibitory signals that actively counter those produced by CD28. CTLA4 can also function in a ligand-independent manner.?CTLA-4 regulates the activation of pathogenic T cells by directly modulating T cell receptor signaling (i.e. TCR-zeta chain phosphorylation) as well as downstream biochemical signals (i.e. ERK activation). The cytoplasmic region of CTLA4 contains a tyrosine motif YVKM and a proline rich region. After TCR stimulation, it undergoes tyrosine phosphorylation by src kinases, inducing surface retention
The Programmed cell death protein 1 (PD-1) is one of the negative regulators of TCR signaling. PD-1 may exert its effects on cell differentiation and survival directly by inhibiting early activation events that are positively regulated by CD28 or indirectly through IL-2. PD-1 ligation inhibits the induction of the cell survival factor Bcl-xL and the expression of transcription factors associated with effector cell function, including GATA-3, Tbet, and Eomes. PD-1 exerts its inhibitory effects by bringing phosphatases SHP-1 and SHP-2 into the immune synapse, leading to dephosphorylation of CD3-zeta chain, PI3K and AKT
Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase
Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c).\nThe tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells