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 Cellprojection, axon Perikaryon Cytoplasmic vesicle, secretoryvesicle, synaptic vesicle membrane Cell junction, synapse, synaptosome Cell junction, synapse,postsynaptic cell membrane, postsynaptic density Note=Is rapidly internalized whendendritic cells are stimulated with the TLR9 ligand cytidine-phosphate-guanosine (CpG) (PubMed:26231120) Detected in apunctate pattern along neurites and axon growth cones (Bysimilarity)
Function (UniProt annotation)
Cell surface receptor that binds to glycosaminoglycans,including chondroitin sulfate proteoglycans and heparan sulfateproteoglycan (PubMed:21454754) Binding to chondroitin sulfate andheparan sulfate proteoglycans has opposite effects on PTPRSoligomerization and regulation of neurite outgrowth Contributesto the inhibition of neurite and axonal outgrowth by chondroitinsulfate proteoglycans, also after nerve transection Plays a rolein stimulating neurite outgrowth in response to the heparansulfate proteoglycan GPC2 Required for normal brain development,especially for normal development of the pituitary gland and theolfactory bulb Functions as tyrosine phosphatase(PubMed:8524829) Mediates dephosphorylation of NTRK1, NTRK2 andNTRK3 (By similarity) Plays a role in down-regulation ofsignaling cascades that lead to the activation of Akt and MAPkinases (By similarity) Down-regulates TLR9-mediated activationof NF-kappa-B, as well as production of TNF, interferon alpha andinterferon beta (PubMed:26231120)
Catalytic Activity (UniProt annotation)
Protein tyrosine phosphate + H(2)O = proteintyrosine + phosphate
Proteoglycans are major components of the extracellular matrix. In cartilage the matrix constitutes more than 90% of tissue dry weight. Proteoglycans are proteins substituted with glycosaminoglycans (GAGs), linear polysaccharides consisting of a repeating disaccharide, generally of an acetylated amino sugar alternatingwith a uronic acid. Most proteoglycans are located in the extracellularspace. Proteoglycans are highly diverse, both in terms of the core proteins and the subtypes of GAG chains, namely chondroitin sulfate (CS), keratan sulfate (KS), dermatan sulfate (DS) and heparan sulfate (HS). Hyaluronan is a non-sulfated GAG whose molecular weight runs into millions of Dalton; in articular cartilage, a single hyaluronan molecule can hold upto 100 aggrecan molecules and these aggregates are stabilized by a link protein
Like neurexins, Receptor-like protein tyrosine phosphatases (RPTPs) make trans-synaptic adhesion complexes with multiple postsynaptic binding partners to regulate synapse organization. The type IIa RPTPs include three members, Receptor-type tyrosine-protein phosphatase F (PTPRF) sometimes referred to as leukocyte common antigen-related (LAR), Receptor-type tyrosine-protein phosphatase sigma (PTPRS) and Receptor-type tyrosine-protein phosphatase delta (PTPRD). These proteins contain typical cell adhesion immunoglobulin-like (Ig) and fibronectin III (FNIII) domains, suggesting the involvement of RPTPs in cell-cell and cell-matrix interactions. To date, six different types of postsynaptic organizers for type-IIa RPTPs have been reported: interleukin-1 receptor accessory protein (IL1RAP, IL-1RAcP) (Yoshida et al. 2012), IL-1RAcP-like-1 (IL1RAPL1) (Yoshida et al. 2011), Neurotrophin receptor tyrosine kinase 3 (NTRK3, TrkC) (Takahashi et al. 2011), Leucine-rich repeat-containing protein 4B (LRRC4B, Netrin-G ligand-3, NGL-3) (Woo et al. 2009, Kwon et al. 2010), the Slit- and Trk-like (Slitrk) family proteins (Takahashi et al. 2012, Yim et al. 2013, Yamagata et al. 2015) and the liprins (Serra-Pagès et al. 1998, Dunah et al. 2005)
Recruitment of receptors and ion channels to the postsynaptic membrane is the last step in synapse formation. Many of these proteins interact directly or indirectly with postsynaptic density-95 (PSD95)/Discs large/zona occludens-1 (PDZ) proteins, thus linking them to the postsynaptic scaffold and providing a mechanism for both retaining the protein at the synapse and keeping its proximity to signaling molecules known to associate with PDZ proteins (Wang et al. 2006, Morimura et al. 2006, Ko et al. 2006, Nourry et al. 2003, Kim & Sheng 2004, Montgomery et al. 2004, Sheng and Kim 2011). The synaptic adhesion-like molecules (SALM) family belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules, alternatively referred to as LRFN (leucine-rich repeat and fibronectin III domain-containing) is synapse adhesion molecule linked to NMDA and AMPA receptors. It includes five known members (SALMs 1-5 or LRFN1-5), which have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation. SALM proteins are distributed to both dendrites and axons in neurons (Ko et al. 2006, Wang et al. 2006, Sebold et al. 2012). The family members, SALM1-SALM5, have a single transmembrane (TM) domain and contain extracellular leucine-rich repeats, an Ig C2 type domain, a fibronectin type III domain, and an intracellular postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 (PDZ) binding domain, which is present on all members except SALM4 and SALM5 (Ko et al. 2006, Wang et al.2006, Morimura et al. 2006)
NTRK3 (TRKC) belongs to the family of neurotrophin receptor tyrosine kinases, which also includes NTRK1 (TRKA) and NTRK2 (TRKB). Neurotrophin-3 (NTF3, also known as NT-3) is the ligand for NTRK3. Similar to other NTRK receptors and receptor tyrosine kinases in general, ligand binding induces receptor dimerization followed by trans-autophosphorylation on conserved tyrosines in the intracellular (cytoplasmic) domain of the receptor (Lamballe et al. 1991, Philo et al. 1994, Tsoulfas et al. 1996, Yuen and Mobley 1999, Werner et al. 2014). These conserved tyrosines serve as docking sites for adaptor proteins that trigger downstream signaling cascades. Signaling through PLCG1 (Marsh and Palfrey 1996, Yuen and Mobley 1999, Huang and Reichardt 2001), PI3K (Yuen and Mobley 1999, Tognon et al. 2001, Huang and Reichardt 2001, Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008) and RAS (Marsh and Palfrey 1996, Gunn-Moore et al. 1997, Yuen and Mobley 1999, Gromnitza et al. 2018), downstream of activated NTRK3, regulates cell survival, proliferation and motility.
In the absence of its ligand, NTRK3 functions as a dependence receptor and triggers BAX and CASP9-dependent cell death (Tauszig-Delamasure et al. 2007, Ichim et al. 2013).
NTRK3 was reported to activate STAT3 through JAK2, but the exact mechanism has not been elucidated (Kim et al. 2016). NTRK3 was reported to interact with the adaptor protein SH2B2, but the biological role of this interaction has not been determined (Qian et al. 1998).
Receptor protein tyrosine phosphatases PTPRO and PTPRS (PTPsigma) negatively regulate NTRK3 signaling by dephosphorylating NTRK3 (Beltran et al. 2003, Faux et al. 2007, Hower et al. 2009, Tchetchelnitski et al. 2014). In addition to dephosphorylation of NTRK3 in-cis, the extracellular domain of pre-synaptic PTPRS can bind in-trans to extracellular domain of post-synaptic NTRK3, contributing to synapse formation (Takahashi et al. 2011, Coles et al. 2014)
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