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
Cell membrane Endosome membrane Early endosome membrane Cell projection, axon Cell projection, dendrite Cytoplasm, perinuclear region Note=Internalized to endosomesupon ligand-binding
Function (UniProt annotation)
Receptor tyrosine kinase involved in the development andthe maturation of the central and the peripheral nervous systemsthrough regulation of neuron survival, proliferation, migration,differentiation, and synapse formation and plasticity Receptorfor BDNF/brain-derived neurotrophic factor and NTF4/neurotrophin-4 Alternatively can also bind NTF3/neurotrophin-3 which is lessefficient in activating the receptor but regulates neuron survivalthrough NTRK2 Upon ligand-binding, undergoes homodimerization,autophosphorylation and activation Recruits, phosphorylatesand/or activates several downstream effectors including SHC1,FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlappingsignaling cascades Through SHC1, FRS2, SH2B1, SH2B2 activates theGRB2-Ras-MAPK cascade that regulates for instance neuronaldifferentiation including neurite outgrowth Through the sameeffectors controls the Ras-PI3 kinase-AKT1 signaling cascade thatmainly regulates growth and survival Through PLCG1 and thedownstream protein kinase C-regulated pathways controls synapticplasticity Thereby, plays a role in learning and memory byregulating both short term synaptic function and long-termpotentiation PLCG1 also leads to NF-Kappa-B activation and thetranscription of genes involved in cell survival Hence, it isable to suppress anoikis, the apoptosis resulting from loss ofcell-matrix interactions May also play a role in neutrophin-dependent calcium signaling in glial cells and mediatecommunication between neurons and glia
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.
The Ras proteins are GTPases that function as molecular switches for signaling pathways regulating cell proliferation, survival, growth, migration, differentiation or cytoskeletal dynamism. Ras proteins transduce signals from extracellular growth factors by cycling between inactive GDP-bound and active GTP-bound states. The exchange of GTP for GDP on RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated RAS (RAS-GTP) regulates multiple cellular functions through effectors including Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide-dissociation stimulator (RALGDS).
The phosphatidylinositol 3' -kinase(PI3K)-Akt signaling pathway is activated by many types of cellular stimuli or toxic insults and regulates fundamental cellular functions such as transcription, translation, proliferation, growth, and survival. The binding of growth factors to their receptor tyrosine kinase (RTK) or G protein-coupled receptors (GPCR) stimulates class Ia and Ib PI3K isoforms, respectively. PI3K catalyzes the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) at the cell membrane. PIP3 in turn serves as a second messenger that helps to activate Akt. Once active, Akt can control key cellular processes by phosphorylating substrates involved in apoptosis, protein synthesis, metabolism, and cell cycle.
Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory.
Alcoholism, also called dependence on alcohol (ethanol), is a chronic relapsing disorder that is progressive and has serious detrimental health outcomes. As one of the primary mediators of the rewarding effects of alcohol, dopaminergic ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) have been identified. Acute exposure to alcohol stimulates dopamine release into the NAc, which activates D1 receptors, stimulating PKA signaling and subsequent CREB-mediated gene expression, whereas chronic alcohol exposure leads to an adaptive downregulation of this pathway, in particular of CREB function. The decreased CREB function in the NAc may promote the intake of drugs of abuse to achieve an increase in reward and thus may be involved in the regulation of positive affective states of addiction. PKA signaling also affects NMDA receptor activity and may play an important role in neuroadaptation in response to chronic alcohol exposure.
TRK receptors can also be activated by at least two G-protein-coupled receptors (GPCR), the adenosine A2a receptor and the PACAP type I receptor, without involvement of neurotrophins. Activity of both receptors is mediated by G proteins that activate adenyl cyclase. How this leads to TRKA activation has not been fully elucidated, although a SRC-family tyrosine kinase and intracellular Ca2+ appear to play a role. TRKA activation through GPCRs occurs with slow kinetics (over 1 hr adenosine or PACAP treatment is required) in an intracellular location (probably the Golgi apparatus), and requires transcriptional and protein synthesis events that may influence the processing and activation of the receptors. GPCR-mediated transactivation of TRK receptors causes the preferential activation of AKT versus ERKs. This leads to a cell survival response
Signaling by the neurotrophin receptor tyrosine kinase NTRK2 (TRKB) can be activated by binding to brain-derived neurotrophic factor (BDNF), which functions as a ligand for NTRK2 (Soppet et al. 1991, Klein et al. 1991). Binding to BDNF triggers NTRK2 dimerization (Ohira et al. 2001) and trans-autophosphorylation of NTRK2 dimers on conserved tyrosine residues in the cytoplasmic tail of the receptor (Guiton et al. 1994, Minichiello et al. 1998, McCarty and Feinstein 1999). Phosphorylated tyrosine residues subsequently serve as docking sites for recruitment of effector proteins that trigger downstream signaling cascades
Neurotrophin receptor tyrosine kinase NTRK2 (TRKB) is a low affinity receptor for neurotrophin-3 (NTF3, also known as NT-3) (Soppet et al. 1991). NTF3 predominantly functions as the ligand for the NTRK3 (TRKC) receptor (Marsh and Palfrey 1996). Binding to NTF3 can trigger NTRK2 dimerization (Ohira et al. 2001) and trans-autophosphorylation of NTRK2 dimers on conserved tyrosine residues in the cytoplasmic tail of the receptor (Middlemas et al. 1994). The efficacy of this process, however, is low in comparison to NTRK2 activation by BDNF and NTF3, and downstream signaling has not been studied
Signaling by the neurotrophin receptor tyrosine kinase NTRK2 (TRKB) can be activated by binding to neurotrophin-4 (NTF4, also known as NT-4), which functions as a ligand for NTRK2 (Klein et al. 1992, Ip et al. 1993, Ohira et al. 2001). Binding to NTF4 triggers NTRK2 dimerization (Ohira et al. 2001) and trans-autophosphorylation of NTRK2 dimers on conserved tyrosine residues in the cytoplasmic tail of the receptor (Minichiello et al. 1998). Phosphorylated tyrosine residues subsequently serve as docking sites for recruitment of effector proteins that trigger downstream signaling cascades
Activation of the neurotrophin receptor NTRK2 (TRKB) by BDNF or NTF4 triggers downstream RAS signaling. The best studied mechanism for activation of RAS signaling downstream of NTRK2 is through SHC1-mediated recruitment of the GRB2:SOS1 complex, triggering SOS1-mediated guanine nucleotide exchange on RAS and formation of active RAS:GTP complexes (Minichiello et al. 1998, McCarthy and Feinstein 1999, Yuen and Mobley 1999)
Activation of the neurotrophin receptor NTRK2 (TRKB) by BDNF or NTF4 triggers downstream PLCgamma (PLCG1) signaling, resulting in formation of secondary messengers DAG and IP3 (Eide et al. 1996, Minichiello et al. 1998, McCarthy and Feinstein 1999, Yuen and Mobley 1999, Minichiello et al. 2002, Yamada et al. 2002)
Neurotrophin receptor NTRK2 (TRKB), activated by BDNF or NTF4, activates PI3K, resulting in formation of the PIP3 secondary messenger. PIP3 activates AKT signaling, and AKT signaling activates mTOR signaling (Yuen and Mobley 1999, Cao et al. 2013)
Adapter proteins FRS2 and FRS3 can both bind to the cytoplasmic tail of activated NTRK2 (TRKB) receptor, which is followed by NTRK2-mediated phosphorylation of FRS2 and FRS3. NTRK2 signaling through FRS3 has been poorly characterized (Easton et al. 1999, Yuen and Mobley 1999, Dixon et al. 2006, Zeng et al. 2014). Phosphorylated FRS2 is known to recruit GRB2 (presumably in complex with SOS1) and PTPN11 (SHP2) to activated NTRK2, leading to augmentation of RAS signaling (Easton et al. 1999, Easton 2006)
In mouse brain, Fyn activation downstream of Bdnf-induced Ntrk2 (TrkB) signaling results in increased protein levels of AMPA receptor subunits Gria2 (GluR2), Gria3 (GluR3) and Gria1 (GluR1) without change in mRNA levels (Narisawa-Saito et al. 1999).
BDNF-mediated activation of NTRK2 increases phosphorylation of voltage gated sodium channels by FYN, resulting in decrease of sodium currents (Ahn et al. 2007).
FYN activation downstream of NTRK2 is implicated in olygodendrocyte myelination and contributes to BDNF-induced activation of ERK1/2 (MAPK3/1) through an unknown mechanism (Peckham et al. 2015).
Besides acting downstream of NTRK2, FYN and other SRC kinases, activated by other receptors such as GPCRs, may phosphorylate NTRK2 and enhance its catalytic activity (Rajagopal and Chao 2006, Huang and McNamara 2010)
DOCK3-mediated activation of RAC1 downstream of BDNF-induced signaling by NTRK2 (TRKB) plays a role in axonal growth and regeneration. DOCK3 can be recruited to the plasma membrane to activate RAC1 by binding to NTRK-associated FYN (Namekata et al. 2010). Alternatively, DOCK3 can, upon poorly elucidated RHOG activation by the BDNF:NTRK2 complex, bind to the RHOG:GTP complex and activate RAC1 in an ELMO1-dependent manner (Namekata et al. 2012)
CDK5, in complex with its activator CDK5R1 (p35), binds to BDNF-activated NTRK2 (TRKB). NTRK2 promotes CDK5 catalytic activity by phosphorylating CDK5 at tyrosine residue Y15 (Cheung et al. 2007), although CDK5 can also be phosphorylated at Y15 independently of NTRK2 (Zhao et al. 2009). CDK5 phosphorylates serine residue S479 of NTRK2 (corresponds to S478 in mouse and rat) (Cheung et al. 2007, Zhao et al. 2009). Phosphorylation of NTRK2 at S479 is needed for BDNF-triggered dendritic growth (Cheung et al. 2007), hippocampal long-term potentiation (LTP) and spatial memory (Lai et al. 2012). These processes involve NTRK2-mediated activation of RHO GTPases RAC1 (Lai et al. 2012) and possibly CDC42 (Cheung et al. 2007). In cultured isolated neurons, phosphorylation at S479 affects localization of NTRK2 (Zhao et al. 2009), but this does not appear to be the case in vivo (Lai et al. 2012).
CDK5-mediated phosphorylation of NTRK2 was suggested to influence the level of AKT activity, downstream mTOR signaling and DLG4 (PSD-95) expression, but further elucidation is needed (Lai et al. 2012).
Signaling by TRKB and CDK5 plays a role in inflammation induced hypersensitivity to heat-triggered pain in rats (Zhang et al. 2014)
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