WNT5:FZD7-mediated leishmania damping (Homo sapiens)

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1, 3, 6, 7, 17...249, 13-16, 30...2, 3214-16, 3021, 35128, 9, 18, 19, 23...11, 25, 414, 5, 10, 20, 26...MacrophagenucleoluscytosolN4GlycoAsn-PalmS WNT5A(36-380) WNT5:FZD7p-S63,S73-JUNWNT5:FZD7:pp-DVLp-T,Y-MAPK8p-T,Y-MAPK8O2.-NADP+ATPO2GTP ATPNOX1 NOXA1 p-DVL3 CYBA FZD7 unknown kinaseCYBA p-DVLpp-DVL3 N4GlycoAsn-PalmS WNT5A(36-380) NOX1complex:WNT5:FZD7:pp-DVL:RAC1:GTPp-DVL3 NADPHADPFZD7 RAC1 JUNN4GlycoAsn-PalmS WNT5A(36-380) p-S-DVL1 NOX1 Complexpp-DVL2 H+NOXO1 pp-DVL1 N4GlycoAsn-PalmS WNT5A(36-380) ATPp-DVL2 p-DVL2 RAC1:GTPADPpp-DVL1 ADPMAPK8pp-DVL3 N4GlycoAsn-PalmSWNT5A(36-380)FZD7pp-DVL2 FZD7 FZD7 pp-DVL3 GTP NOX1 GTP NOXO1 RAC1 FZD7 WNT5:FZD7:pp-DVL:RAC1:GTPp-S-DVL1 WNT5:FZD7:p-DVLpp-DVL1 RAC1 NOXA1 N4GlycoAsn-PalmS WNT5A(36-380) pp-DVL2 16, 3014, 15


Description

Wnt-5a (WNT5) is known for being a highly specific regulated gene in response to microbial infection (Blumenthal et al. 2006, Pereira et al. 2008 & Ljungberg et al. 2019) including leishmaniasis (Chakraborty et al. 2017), where it seems to be involve in mechanisms that dampen the parasite load within main host macrophages (Chakraborty et al. 2017). In addition, WNT5 is a highly responsive gene in human macrophages present in chronic diseases such as rheumatoid arthritis (Sen et al. 2000), cancer (Pukrop et al. 2006), atherosclerosis (Christman et al. 2008) and obesity (Ouchi et al. 2010 & Ljungberg et al. 2019).

Frizzled-7 (FZD7) acts as a receptor of WNT5 which, upon binding, is implicated in the initiation of the non-canonical WNT pathway that ends up in the re-accommodation of the cytoskeleton to allow a process called planar cell polarity (PCP) (Ljungberg et al. 2019). The activation of the WNT5:FZD7 non-canonical signalling cascade that drives PCP is being studied for its involvement in inflammatory responses (Shao et al. 2016). Treatment of RAW264.7 macrophages with recombinant Wnt5a induced NADPH oxidase-mediated ROS production, which has been suggested to contribute to the macrophage control of L. donovani. Consequently, detailed understanding of how WNT signaling network defines host responses to infection could be important to identify potential targets (Ljungberg et al. 2019). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9673324
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Murillo, Julieth, Jassal, Bijay

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Bibliography

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History

CompareRevisionActionTimeUserComment
114959view16:48, 25 January 2021ReactomeTeamReactome version 75
113403view11:47, 2 November 2020ReactomeTeamReactome version 74
112824view18:29, 9 October 2020DeSlOntology Term : 'Leishmaniasis pathway' added !
112771view16:17, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
CYBA ProteinP13498 (Uniprot-TrEMBL)
FZD7 ProteinO75084 (Uniprot-TrEMBL)
FZD7ProteinO75084 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
JUNProteinP05412 (Uniprot-TrEMBL)
MAPK8ProteinP45983 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A(36-380)ProteinP41221 (Uniprot-TrEMBL)
N4GlycoAsn-PalmS WNT5A(36-380) ProteinP41221 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NOX1 complex:WNT5:FZD7:pp-DVL:RAC1:GTPComplexR-HSA-9673791 (Reactome)
NOX1 ComplexComplexR-HSA-5668698 (Reactome)
NOX1 ProteinQ9Y5S8 (Uniprot-TrEMBL)
NOXA1 ProteinQ86UR1 (Uniprot-TrEMBL)
NOXO1 ProteinQ8NFA2 (Uniprot-TrEMBL)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GTPComplexR-HSA-442641 (Reactome)
WNT5:FZD7:p-DVLComplexR-HSA-9673309 (Reactome)
WNT5:FZD7:pp-DVL:RAC1:GTPComplexR-HSA-9675729 (Reactome)
WNT5:FZD7:pp-DVLComplexR-HSA-9673343 (Reactome)
WNT5:FZD7ComplexR-HSA-9673287 (Reactome)
p-DVL2 ProteinO14641 (Uniprot-TrEMBL)
p-DVL3 ProteinQ92997 (Uniprot-TrEMBL)
p-DVLComplexR-HSA-3858479 (Reactome)
p-S-DVL1 ProteinO14640 (Uniprot-TrEMBL)
p-S63,S73-JUNProteinP05412 (Uniprot-TrEMBL)
p-T,Y-MAPK8ProteinP45983 (Uniprot-TrEMBL)
pp-DVL1 ProteinO14640 (Uniprot-TrEMBL)
pp-DVL2 ProteinO14641 (Uniprot-TrEMBL)
pp-DVL3 ProteinQ92997 (Uniprot-TrEMBL)
unknown kinaseR-HSA-451336 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9673284 (Reactome)
ADPArrowR-HSA-9673346 (Reactome)
ADPArrowR-HSA-9673789 (Reactome)
ATPR-HSA-9673284 (Reactome)
ATPR-HSA-9673346 (Reactome)
ATPR-HSA-9673789 (Reactome)
FZD7R-HSA-9673349 (Reactome)
H+ArrowR-HSA-9673797 (Reactome)
JUNR-HSA-9673789 (Reactome)
MAPK8R-HSA-9673284 (Reactome)
N4GlycoAsn-PalmS WNT5A(36-380)R-HSA-9673349 (Reactome)
NADP+ArrowR-HSA-9673797 (Reactome)
NADPHR-HSA-9673797 (Reactome)
NOX1 complex:WNT5:FZD7:pp-DVL:RAC1:GTPArrowR-HSA-9673794 (Reactome)
NOX1 complex:WNT5:FZD7:pp-DVL:RAC1:GTPmim-catalysisR-HSA-9673797 (Reactome)
NOX1 ComplexR-HSA-9673794 (Reactome)
O2.-ArrowR-HSA-9673797 (Reactome)
O2R-HSA-9673797 (Reactome)
R-HSA-9673284 (Reactome) Ras-related C3 botulinum toxin substrate 1 (RAC1) activation was described as essential for p75NTR to induce MAPK8 (aka JNK) and apoptosis in cortical oligodendrocytes (Bazenet et al. 1998). The simultaneous activation of TRKA counteracts the apoptotic action of p75, by modulating the kinetics of p75-mediated RAC activation.
R-HSA-9673288 (Reactome) WNT-dependent activation of dishevelled proteins (DVL) induces the activation of RAC and the formation of a RAC:DVL complex in HEK293 cells (Habas et al, 2003). Activation of RAC and stimulation of PCP/CE signaling depends on the DEP but not the DIX domain of DVL (Axelrod et al, 1998; Boutros et al, 1998, Habas et al, 2001, Habas et al, 2003). There are conflicting reports regarding the requirement for the DVL PDZ domain in the WNT-dependent activation of RAC (Habas et al, 2003; Cajanek et al, 2013). Activation of RAC almost certainly involves a RAC-specific GEF activity, potentially associated with DVL. In dopaminergic neurons, TIAM1 has been identified as the GEF for WNT5A- and DVL-dependent activation of RAC (Cajanek et al, 2013), however it is not clear whether this is generally true in other cell types and for other WNT ligands. In some cases, RAC activation correlates with activation of the downstream effector c-Jun N terminal kinase (JNK). This is thought to regulate reorganization of the cytoskeleton but the mechanism of JNK activation is unknown. In other cases, JNK activation appears to be dispensable to the WNT response (Yamanaka et al, 2002; Habas et al, 2003; Rosso et al, 2005; reviewed in Heaseman and Ridley, 2008; Lai et al, 2009).
R-HSA-9673296 (Reactome) The DEP domain of dishevelled proteins (DVL) is required both for planar cell polarization (PCP) signaling and for membrane localization upon WNT activation (Boutros et al, 1998; Axelrod et al, 2001; Rothbacher et al, 2000, Wong et al, 2000; Park et al, 2005; Witzel et al, 2006). Although DVL interacts with FZD through its PDZ domain, disruption of this binding interface does not interfere with non-canonical signaling (Wong et al, 2003). Membrane recruitment of DVL and establishment of PCP may also rely on other interacting partners (Lee et al, 2007; Li et al, 2013).
R-HSA-9673322 (Reactome) NRAGE, NRIF, NADE, TRAF6 mediate, through unclear mechanisms, MAPK8 (aka JNK) activation by threonine and tyrosine phosphorylation. While active (phosphorylated) MAPK8 moves to the nucleus and phosphorylates transcription factors such as c-JUN and ATF2, these have not been implicated in p75-mediated cell death. p75 activates the intrinsic caspase pathway (involving mitochondrial release of cytochrome c, Apaf-1, and caspases-9) rather than the extrinsic (caspase-8) pathway activated by most other death receptors (Troy et al. 2002).
R-HSA-9673346 (Reactome) In response to WNT signaling, dishevelled (DVL) proteins are phosphorylated within the C-terminus. This site appears to be common for both canonical and non-canonical WNT signaling as a similar phosphorylation pattern is observed upon stimulation with WNT1 and WNT5A and no discernable supershifted phosphoform is detected upon simultaneous treatment with both ligands (Gonzalez-Sancho et al, 2004). The kinase responsible for this phosphorylation has not been identified, although CK2, CK1 delta and epsilon and PAR1 have all been shown to phosphorylate DVL in vitro and in vivo under varying conditions (reviewed in Gao and Chen, 2010). WNT3a or WNT5a-induced phosphorylation sites are Ser594, Thr595 and Ser597 in Dvl2 (Gonzalez-Sancho et al. 2013).
R-HSA-9673349 (Reactome) Non-canonical WNT5A pathways (the ones that do not induce the activation of β-catenin) are usually initiated by the binding of WNT5A to FZD receptors, including FZD7 (Nishita et al. 2010 & Anastas et al. 2014).
R-HSA-9673789 (Reactome) JNK (c-Jun N-terminal Kinase) phosphorylates several transcription factors including c-Jun after translocation to the nucleus.
R-HSA-9673794 (Reactome) Activated RAC1 (RAC1:GTP) binds NADPH oxidase NOX1 complex composed of NOX1, NOXA1, NOXO1 and CYBA (p22phox). RAC1 directly interacts with a conserved region in NOX1 and with tetratricopeptide repeats in NOXA1 (Takeya et al. 2003, Park et al. 2006, Cheng et al. 2006, Miyano et al. 2006, Kao et al. 2008)
R-HSA-9673797 (Reactome) The activity of the non-phagocytic NADPH oxidase 1 (NOX1) complex, composed of NOX1, NOXA1, NOXO1 and CYBA, is greatly enhanced upon RAC1:GTP binding, resulting in production of the superoxide O2- which can serve as a second messenger (Takeya et al. 2003, Miyano et al. 2006, Park et al. 2006, Cheng et al. 2006).
RAC1:GTPR-HSA-9673288 (Reactome)
WNT5:FZD7:p-DVLArrowR-HSA-9673296 (Reactome)
WNT5:FZD7:p-DVLR-HSA-9673346 (Reactome)
WNT5:FZD7:pp-DVL:RAC1:GTPArrowR-HSA-9673288 (Reactome)
WNT5:FZD7:pp-DVL:RAC1:GTPR-HSA-9673794 (Reactome)
WNT5:FZD7:pp-DVL:RAC1:GTPmim-catalysisR-HSA-9673284 (Reactome)
WNT5:FZD7:pp-DVLArrowR-HSA-9673346 (Reactome)
WNT5:FZD7:pp-DVLR-HSA-9673288 (Reactome)
WNT5:FZD7ArrowR-HSA-9673349 (Reactome)
WNT5:FZD7R-HSA-9673296 (Reactome)
p-DVLR-HSA-9673296 (Reactome)
p-S63,S73-JUNArrowR-HSA-9673789 (Reactome)
p-T,Y-MAPK8ArrowR-HSA-9673284 (Reactome)
p-T,Y-MAPK8ArrowR-HSA-9673322 (Reactome)
p-T,Y-MAPK8R-HSA-9673322 (Reactome)
p-T,Y-MAPK8mim-catalysisR-HSA-9673789 (Reactome)
unknown kinasemim-catalysisR-HSA-9673346 (Reactome)
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