Search results for JAK2

Showing 26 results out of 408

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Protein (5 results from a total of 10)

Identifier: R-HSA-210620
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: JAK2: O60674
Identifier: R-HSA-2002372
Species: Homo sapiens
Compartment: endosome lumen
Primary external reference: UniProt: JAK2: O60674
Identifier: R-HSA-5211269
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: JAK2: O60674
Identifier: R-HSA-210621
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: JAK2: O60674
Identifier: R-HSA-873799
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: JAK2: O60674

Reaction (5 results from a total of 150)

Identifier: R-HSA-873919
Species: Homo sapiens
Compartment: cytosol, plasma membrane
IFN-gamma binding to the receptor complex, induces JAK2 autophosphorylation and activation. Like all protein tyrosine kinases (PTKs) JAK2 activity also depends on the phosphorylation of tandem tyrosine residues within the activation loop that results in the removal of the activation loop from the active site. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ) of which phosphorylation of tyrosine 1007 is essential for kinase activity. Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only tyrosine 1007 is represented in the reaction.
Identifier: R-HSA-1433418
Species: Homo sapiens
Compartment: plasma membrane, cytosol, extracellular region
SCF induces rapid and transient autophosphorylation of JAK2 bound to c-KIT. JAKs bound to activated, dimerized receptors cross-phosphorylate and thereby activate each other. Multiple phosphorylation sites have been identified in JAK2 (tyrosines 221, 570, 868, 966, 972, 1007 and 1008 ). Phosphorylation of tyrosine 1007 is essential for kinase activity (Feng et al 1997, Argetsinger et al. 2004, 2010). Tyrosine 1007 is in the activation loop and phosphorylation allows access of the catalytic loop to the ATP in the ATP binding domain. Of all the predicted phoshorylation sites only the critical tyrosine 1007 is represented in the reaction.
Identifier: R-HSA-982810
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Similar models explain JAK activation by the cytokine-like hormone receptors (GHR and PRLR) and interleukin receptors. JAK2 activation is believed to occur as mutual transactivation whereby JAK2 bound to one receptor chain phosphorylates JAK2 bound to the other receptor chain in the dimeric receptor. Transactivation is widely accepted (Herrington & Carter-Su 2001) having been originally proposed in the 1990's (Quelle et al. 1994, Hou et al. 2002). JAK phosphorylation is thought to lock the kinase domain in an active state; prior to this JAK2 is held in an inactive state by interactions between its kinase and pseudokinase domains (Giordanetto & Kroemer 2002). Although there are structures of JAK kinase domains (e.g. Lucet et al. 2006), no complete JAK structures are available and the activation mechanism remains poorly understood (Brooks & Waters 2010). The trigger for JAK activation is believed to be a conformational change in the receptor when ligand is bound, leading to a rotation of the cytoplasmic regions which brings the catalytic domains of bound JAK2 molecules into close proximity and frees them from inhibition by the pseudokinase domains. Supporting observations for cytokine-like hormone receptors include: JAK2 becomes tyrosine phosphorylated as a consequence of GHR activation by GH (Argetsinger et al. 1993); JAK2 is activated following PRLR activation (Campbell et al. 1994, Rui et al. 1994); forced dimerization of GH receptor domains is sufficient to activate signaling (Behncken et al. 2000); phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006); JAK autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the Y1007 phosphorylation is represented in this reaction.
Identifier: R-NUL-8950050
Species: Mus musculus, Homo sapiens
Compartment: cytosol, plasma membrane
This reaction was inferred from the corresponding reaction "IL12RB2 binds Jak2" in species Homo sapiens. Murine Tyrosine protein kinase Jak2 (JAK2) directly associates with the intracellular domain of the human Interleukin 12 receptor subunit beta 2 (IL12RB2) . Interleukin 12 receptor subunit beta 1 (IL12RB1) and Non receptor tyrosine protein kinase TYK2 (TYK2) are not required ((Zou et al 1997, Floss et al. 2016, Yamamoto et al. 1999).
Identifier: R-HSA-879910
Species: Homo sapiens
Compartment: cytosol, plasma membrane
JAK2 is tyrosine phosphorylated in response to IL-3 (Silvennoinen et al. 1993), GM-CSF (Quelle et al. 1994) and IL-5 (Cornelis et al. 1995) leading to kinase activity. Although structures of JAK kinase domains exist (e.g. Lucet et al. 2006) no complete structures of Janus kinases (JAKs) are available and the activation mechanism is poorly understood. Activation is believed to be a consequence of conformational changes, propagated from conformational changes in the common beta chain (Bc) following alpha-beta dimerization. This is believed to result in a trans-activation event whereby JAKs bound to activated, dimerized receptors phosphorylate and thereby activate each other (Quelle et al. 1994, Hou et al. 2002). This model is similar to IL2R activation of JAK1/3. In addition to the observed activation of JAK2 following stimulation with IL-3, IL-5 or GM-CSF, other supporting observations include: phosphorylation of JAK2 at Y1007 is critical for kinase activation (Feng et al. 1997, Lucet et al. 2006) and autophosphorylation at several other sites appears to regulate activity (e.g. Feener et al. 2004, Argetsinger et al. 2004, 2010). Only the critical Y1007 phosphorylation is represented for this reaction.

Constitutive activation of JAK2 resulting from the V617F mutation is present in over 95% of Polycythemia Vera patients (Dusa et al. 2010). F595 is indispensible for constitutive activation by V617F, but not for JAK2 activation, suggesting that this is not part of the cytokine-induced mechansim of JAK2 activation.

Complex (5 results from a total of 208)

Identifier: R-HSA-912306
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-912319
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-893545
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-913415
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-914175
Species: Homo sapiens
Compartment: plasma membrane

Set (5 results from a total of 23)

Identifier: R-HSA-8987151
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9674547
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-913399
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-913405
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-6788568
Species: Homo sapiens
Compartment: cytosol

Pathway (5 results from a total of 16)

Identifier: R-HSA-9027283
Species: Homo sapiens
STAT5 (STAT5A or STAT5B) directly binds the phosphorylated cytoplasmic domain of EPOR, where it is phosphorylated by JAK2 and LYN (Oda et al. 1998, inferred from mouse homologs, reviewed in Kuhrt and Wojchowski 2015). Phosphorylated STAT5 then dissociates from EPOR, dimerizes, and transits to the nucleus where it activates gene expression.
Identifier: R-HSA-2979096
Species: Homo sapiens
Similar to NOTCH1, NOTCH2 is activated by Delta-like and Jagged ligands (DLL/JAG) expressed in trans on a neighboring cell (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). The activation triggers cleavage of NOTCH2, first by ADAM10 at the S2 cleavage site (Gibb et al. 2010, Shimizu et al. 2000), then by gamma-secretase at the S3 cleavage site (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 subsequently traffics to the nucleus where it acts as a transcription regulator.

While DLL and JAG ligands are well established, canonical NOTCH2 ligands, there is limited evidence that NOTCH2, similar to NOTCH1, can be activated by CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003). MDK (midkine), which plays an important role in epithelial to mesenchymal transition, can also activate NOTCH2 signaling and is able to bind to the extracellular domain of NOTCH2, but the exact mechanism of MDK-induced NOTCH2 activation has not been elucidated (Huang et al. 2008, Gungor et al. 2011).
Identifier: R-HSA-1980145
Species: Homo sapiens
Compartment: plasma membrane, cytosol, nucleoplasm
NOTCH2 is activated by binding Delta-like and Jagged ligands (DLL/JAG) expressed in trans on neighboring cells (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). In trans ligand-receptor binding is followed by ADAM10 mediated (Gibb et al. 2010, Shimizu et al. 2000) and gamma secretase complex mediated cleavage of NOTCH2 (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 traffics to the nucleus where it acts as a transcriptional regulator. For a recent review of the cannonical NOTCH signaling, please refer to Kopan and Ilagan 2009, D'Souza et al. 2010, Kovall and Blacklow 2010. CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003) and MDK (midkine) (Huang et al. 2008, Gungor et al. 2011), which plays an important role in epithelial-to-mesenchymal transition, can also bind NOTCH2 and activate NOTCH2 signaling.

In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). The NICD2:RBPJ:MAML complex activates transcription from RBPJ binding promoter elements (RBEs) (Wu et al. 2000). NOTCH2 coactivator complexes directly stimulate transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets. NOTCH2 but not NOTCH1 coactivator complexes, stimulate FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development (Hubmann et al. 2002). NOTCH2 coactivator complexes together with CREBP1 and EP300 stimulate transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T cells (Maekawa et al. 2008).

NOTCH2 gene expression is differentially regulated during human B-cell development, with NOTCH2 transcripts appearing at late developmental stages (Bertrand et al. 2000).

NOTCH2 mutations are a rare cause of Alagille syndrome (AGS). AGS is a dominant congenital multisystem disorder characterized mainly by hepatic bile duct abnormalities. Craniofacial, heart and kidney abnormalities are also frequently observed in the Alagille spectrum (Alagille et al. 1975). AGS is predominantly caused by mutations in JAG1, a NOTCH2 ligand (Oda et al. 1997, Li et al. 1997), but it can also be caused by mutations in NOTCH2 (McDaniell et al. 2006).


Hajdu-Cheney syndrome, an autosomal dominant disorder characterized by severe and progressive bone loss, is caused by NOTCH2 mutations that result in premature C-terminal NOTCH2 truncation, probably leading to increased NOTCH2 signaling (Simpson et al. 2011, Isidor et al. 2011, Majewski et al. 2011).
Identifier: R-HSA-9034015
Species: Homo sapiens
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).

Identifier: R-HSA-2586552
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Leptin (LEP, OB, OBS), a circulating adipokine, and its receptor LEPR (DB, OBR) control food intake and energy balance and are implicated in obesity-related diseases (recently reviewed in Amitani et al. 2013, Dunmore and Brown 2013, Cottrell and Mercer 2012, La Cava 2012, Marroqui et al. 2012, Paz-Filho et al. 2012, Denver et al. 2011, Lee 2011, Marino et al. 2011, Morton and Schwartz 2011, Scherer and Buettner 2011, Shan and Yeo 2011, Wauman and Tavernier 2011, Dardeno et al. 2010, Bjorbaek 2009, Morris and Rui 2009, Myers et al. 2008), including cancer (Guo et al. 2012), inflammation (Newman and Gonzalez-Perez 2013, Iikuni et al. 2008), and angiogenesis (Gonzalez-Perez et al. 2013).
The identification of spontaneous mutations in the leptin gene (ob or LEP) and the leptin receptor gene (Ob-R, db or LEPR) genes in mice opened up a new field in obesity research. Leptin was discovered as the product of the gene affected by the ob (obesity) mutation, which causes obesity in mice. Likewise LEPR is the product of the gene affected by the db (diabetic) mutation. Leptin binding to LEPR induces canonical (JAK2/STATs; MAPK/ERK 1/2, PI-3K/AKT) and non-canonical signaling pathways (PKC, JNK, p38 MAPK and AMPK) in diverse cell types. The binding of leptin to the long isoform of LEPR (OB-Rl) initiates a phosphorylation cascade that results in transcriptional activation of target genes by STAT5 and STAT3 and activation of the PI3K pathway(not shown here), the MAPK/ERK pathway, and the mTOR/S6K pathway. Shorter LEPR isoforms with truncated intracellular domains are unable to activate the STAT pathway, but can transduce signals by way of activation of JAK2, IRS-1 or ERKs, including MAPKs.
LEPR is constitutively bound to the JAK2 kinase. Binding of LEP to LEPR causes a conformational change in LEPR that activates JAK2 autophosphorylation followed by phosphorylation of LEPR by JAK2. Phosphorylated LEPR binds STAT3, STAT5, and SHP2 which are then phosphorylated by JAK2. Phosphorylated JAK2 binds SH2B1 which then binds IRS1/2, resulting in phosphorylation of IRS1/2 by JAK2. Phosphorylated STAT3 and STAT5 dimerize and translocate to the nucleus where they activate transcription of target genes (Jovanovic et al. 2010). SHP2 activates the MAPK pathway. IRS1/2 activate the PI3K/AKT pathway which may be the activator of mTOR/S6K.
Several isoforms of LEPR have been identified (reviewed in Gorska et al. 2010). The long isoform (LEPRb, OBRb) is expressed in the hypothalamus and all types of immune cells. It is the only isoform known to fully activate signaling pathways in response to leptin. Shorter isoforms (LEPRa, LEPRc, LEPRd, and a soluble isoform LEPRe) are able to interact with JAK kinases and activate other pathways, however their roles in energy homeostasis are not fully characterized.

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Steve Jupe
Designer: Cristoffer Sevilla
JAK2 icon
Tyrosine-protein kinase JAK2
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