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
Receptor tyrosine kinase involved in nervous system andprobably heart development Upon binding of its ligandNTF3/neurotrophin-3, NTRK3 autophosphorylates and activatesdifferent signaling pathways, including the phosphatidylinositol3-kinase/AKT and the MAPK pathways, that control cell survival anddifferentiation
Catalytic Activity (UniProt annotation)
ATP + a [protein]-L-tyrosine = ADP + a[protein]-L-tyrosine phosphate
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.
Malignant transformation of cells requires specific adaptations of cellular metabolism to support growth and survival. In the early twentieth century, Otto Warburg established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. He showed that cancer cells consume a large amount of glucose, maintain high rate of glycolysis and convert a majority of glucose into lactic acid even under normal oxygen concentrations (Warburg's Effects). More recently, it has been recognized that the 'Warburg effect' encompasses a similarly increased utilization of glutamine. From the intermediate molecules provided by enhanced glycolysis and glutaminolysis, cancer cells synthesize most of the macromolecules required for the duplication of their biomass and genome. These cancer-specific alterations represent a major consequence of genetic mutations and the ensuing changes of signalling pathways in cancer cells. Three transcription factors, c-MYC, HIF-1 and p53, are key regulators and coordinate regulation of cancer metabolism in different ways, and many other oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53.
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)
NTRK3 (TRKC) is activated by binding to its ligand neurotrophin-3 (NTF3, also known as NT-3). Ligand binding induces dimerization of NTRK3 and trans-autophosphorylation of dimerized receptors on conserved tyrosine residues in the cytoplasmic tail. Autophosphorylated tyrosines serve as docking sites for binding of adaptor proteins that mediate downstream signaling (Lamballe et al. 1991, Philo et al. 1994, Tsoulfas et al. 1996, Huang and Reichardt 2001, Werner et al. 2014)
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)
The receptor tyrosine kinase NTRK3 (TRKC), when activated by its ligand NTF3 (NT-3), induces PLCG1 phosphorylation, triggering PLCG1 signaling (Marsh and Palfrey 1996, Yuen and Mobley 1999)
Upon activation by NTF3 (NT-3), the receptor tyrosine kinase NTRK3 (TRKC) triggers RAS signaling through adaptor proteins SHC1 and GRB2 (Marsh and Palfrey 1996, Gunn-Moore et al. 1997, Yuen and Mobley 1999). ERK activation downstream of NTRK3 may increase cell motility through WAVE. The mechanism is not known (Gromnitza et al. 2018)
The PI3K complex, composed of PIK3R1 and PIK3CA, co-immunoprecipitates with NTRK3 (TRKC), activated by NTF3 (NT-3) treatment (Yuen and Mobley 1999). Activation of NTRK3 correlates with activating phosphorylation of AKT, the main mediator of PI3K signaling (Tognon et al. 2001, Jin et al. 2008), and is dependent on PI3K activity (Tognon et al. 2001). NTRK3-mediated activation of PI3K signaling depends on SRC activation and the adaptor protein IRS1, but the exact mechanism is not known (Morrison et al. 2002, Lannon et al. 2004, Jin et al. 2008)
When neuronal cells are deprived of the NTRK3 (TRKC) ligand NTF3 (NT-3), NTRK3 functions as a dependence receptor, promoting apoptosis. The pro-apoptotic activity of NTRK3 is implicated in proper nervous system development, by dictating the number of surviving sensory neurons (Tauszig-Delamasure et al. 2007). In the absence of its ligand, NTRK3 undergoes caspase-dependent cleavage (Tauszig-Delamasure et al. 2007), resulting in release of the NTRK3 killer fragment (KF). The NTRK3 KF, in complex with NELFB (COBRA1), inserts into the mitochondrial membrane, promoting cytochrome c release and apoptosome-mediated apoptosis (Ichim et al. 2013)
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