241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Cytoplasm Membrane raft Note=Colocalized withDPP4 in membrane rafts
Function (UniProt annotation)
Involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation Its binding toDPP4 induces T-cell proliferation and NF-kappa-B activation in aT-cell receptor/CD3-dependent manner Activates NF-kappa-B viaBCL10 and IKK Stimulates the phosphorylation of BCL10 Alsoactivates the TORC1 signaling pathway
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.
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.
B cells are an important component of adaptive immunity. They produce and secrete millions of different antibody molecules, each of which recognizes a different (foreign) antigen. The B cell receptor (BCR) is an integral membrane protein complex that is composed of two immunoglobulin (Ig) heavy chains, two Ig light chains and two heterodimers of Ig-alpha and Ig-beta. After BCR ligation by antigen, three main protein tyrosine kinases (PTKs) -the SRC-family kinase LYN, SYK and the TEC-family kinase BTK- are activated. Phosphatidylinositol 3-kinase (PI3K) and phospholipase C-gamma 2 (PLC-gamma 2) are important downstream effectors of BCR signalling. This signalling ultimately results in the expression of immediate early genes that further activate the expression of other genes involved in B cell proliferation, differentiation and Ig production as well as other processes.
DAG and calcium activate protein kinase C beta (PKC-beta, Kochs et al. 1991) which phosphorylates CARMA1 and other proteins (Sommer et al. 2005). Phosphorylated CARMA1 recruits BCL10 and MALT1 to form the CBM complex (Sommer et al. 2005, Tanner et al. 2007) which, in turn, recruits the kinase TAK1 and the IKK complex (Sommer et al. 2005, Shinohara et al. 2005 using chicken cells). TAK1 phosphorylates the IKK-beta subunit, activating it (Wang et al. 2001). The IKK complex then phosphorylates IkB complexed with NF-kappaB dimers in the cytosol (Zandi et al. 1998, Burke et al. 1999, Heilker et al. 1999), resulting in the degradation of IkB (Miyamoto et al. 1994, Traenckner et al. 1994, Alkalay et al. 1995, DiDonato et al. 1995, Li et al. 1995, Lin et al. 1995, Scherer et al. 1995, Chen et al. 1995). NF-kappaB dimers are thereby released and are translocated to the nucleus where they activate transcription (Baeuerle and Baltimore 1988, Blank et al. 1991, Ghosh et al. 2008, Fagerlund et al. 2008)
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)
The increase in intracellular Ca+2 in conjunction with DAG also activates PKC and RasGRP, which inturn contributes to cytokine production by mast cells (Kambayashi et al. 2007). Activation of the FCERI engages CARMA1, BCL10 and MALT1 complex to activate NF-kB through PKC-theta (Klemm et al. 2006, Chen et al. 2007). FCERI stimulation leads to phosphorylation, and degradation of IkB which allows the release and nuclear translocation of the NF-kB proteins. Activation of the NF-kB transcription factors then results in the synthesis of several cytokines. NF-kB activation by FCERI is critical for proinflammatory cytokine production during mast cell activation and is crucial for allergic inflammatory diseases (Klemm et al. 2006)
CLEC7A (also known as Dectin-1) is a pattern-recognition receptor (PRR) expressed by myeloid cells (macrophages, dendritic cells and neutrophils) that detects pathogens by binding to beta-1,3-glucans in fungal cell walls and triggers direct innate immune responses to fungal and bacterial infections. CLEC7A belongs to thetype-II C-type lectin receptor (CLR) family that can mediate its own intracellular signaling. Upon binding particulate beta-1,3-glucans, CLEC7A mediates intracellular signalling through its cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif (Brown 2006). CLEC7A signaling can induce the production of various cytokines and chemokines, including tumour-necrosis factor (TNF), CXC-chemokine ligand 2 (CXCL2, also known as MIP2), interleukin-1beta (IL-1b), IL-2, IL-10 and IL-12 (Brown et al. 2003), it also triggers phagocytosis and stimulates the production of reactive oxygen species (ROS), thus contributing to microbial killing (Gantner et al. 2003, Herre et al. 2004, Underhill et al. 2005, Goodridge at al. 2011, Reid et al. 2009). These cellular responses mediated by CLEC7A rely on both Syk-dependent and Syk-independent signaling cascades. The pathways leading to the Syk-dependent activation of NF-kB can be categorised into both canonical and non-canonical routes (Gringhuis et al. 2009). Activation of the canonical NF-kB pathway is essential for innate immunity, whereas activation of the non-canonical pathway is involved in lymphoid organ development and adaptive immunity (Plato et al. 2013)
Affinity Capture-Western, Co-crystal Structure, Co-localization, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation
Affinity Capture-Western, Co-crystal Structure, Co-localization, Reconstituted Complex, Two-hybrid, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation
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