RANKL/RANK Signaling Pathway (Bos taurus)

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NFKB1FOSRELBCalcineurinCa2+RANKL/RANK Signaling PathwayOsteoclastogenesisNFKB1SYKMAP2K6LYNMITFFHL2MAP2K1RAC1GTPPPTNFRSF11BMAP2K7TRAF6UbTNFSF11GAB2PTNFRSF11ATRAF2TRAF3TRAF5TRAF1PIK3R1NFATC1PIK3R2STAT1PIKBKGIKBKBAKT1PBIKBAPMAPK9PMAP3K7PLCG1PJUNPPTK2PRELAPAKT2PMAPK8PMAPK3PMAPK1PMAPK14PCHUKPMTORPSRCPTNFSF11TNFSF11TNFRSF11ATNFRSF11ATAB2MAP3K7IP1IP3NFATC1RELAPMAPK14CYCYNUCBLPNUCYNUROSCDC42GTPCALCRNFATC1ACP5SQSTM1TNFRSF11AICAM1VCAM1CTSKSPI1PAPSS2NFKB2PNFKB2CYNURELBPProteinProteinmRNALigandReceptorProteinProtein - protein dissociationEnzyme ComplexSmall moleculeInduced activationInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMolecule


Description

RANKL (Receptor activator of nuclear factor-kappa B ligand), RANK (Receptor activator of nuclear factor-kappa B) and the natural decoy receptor of RANKL, OPG (Osteoprotegerin) are three important molecules identified to play a major role in osteoclastogenesis and bone remodelling. They are members of the tumor necrosis factor (TNF) superfamily. OPG was the first molecule to be discovered and proved to inhibit osteoclastogenesis both in vivo and in vitro. Unlike other members of TNF family, OPG lack a transmembrane domain and is secreted as a soluble protein by the cell. RANKL is the only known physiological agonist for its receptor, RANK. Genetic experiments have shown that mice lacking either rankl or rank suffer from severe osteoporosis and defective tooth eruption due to complete lack of osteoclasts. On the contrary, mice deficient of OPG shows osteoporosis due to increased number of osteoclasts. Binding of RANKL to RANK triggers downstream signaling events that leads to the activation of osteoclasts and controlling of lineage commitment. RANKL/RANK signaling is essential for skeletal homoeostasis and its interference leads to inhibition of bone resorption resulting in bone diseases including osteoporosis osteopetrosis and rheumatoid arthritis. RANK being a member of TNF family does not possess any kinase activity. It recruits adaptor molecules to transduce the signal after ligand binding. These adaptor molecules are called TNFR-associated factors or TRAF's that binds to different regions in the cytoplasmic tail of the TNF family receptors and transduces the signal downstream. TRAF6 is the main adaptor molecule which activates NF-κB pathway downstream of RANKL signaling which is required for osteoclastogenesis and osteoclast activation. TRAF6 mutant mice have shown a partial block in osteoclastogenesis and defective activation of mature osteoclasts. Mice lacking NF-κB p50 and p52 proteins have been shown to be osteopetrotic. Catalytic subunits, IκB kinase α and IκB kinase β and the non-catalytic subunit IKKγ (also called NEMO) are also essential for RANKL-RANK signaling and osteoclastogenesis. IKKγ is required for osteoclastogenesis induced by RANKL in mice both in vivo and in vitro whereas IKKα was shown to be required in mice only in in vitro. Several mitogen activated protein kinases (MAPK's) have been shown to be activated downstream of RANK. Studies have shown that pharmacological inhibition of p38 MAPK's blocked RANKL induced osteoclast differentiation. JNK1/2, its upstream kinase MKK7 and c-Jun have also been shown by genetic experiments to be essential for RANKL induced osteoclastogenesis. MAPK1 and MAPK3 phosphorylation was also shown to be dispensable for RANKL mediated osteoclast differentiation in vitro, but another report also show that specific inhibitors to MEK increased RANKL induced osteoclastogenesis suggesting a cross talk between p38 and ERK signaling pathways. NFATc1 is an essential downstream target of RANK. Ca2+ oscillations induced by RANKL activated NFATc1 resulting in terminal differentiation of osteoclasts through the Ca2+- dependent calcineurin pathway. NFATc1 translocates to the nucleus where it interacts with other transcription factors leading to the activation of transcription of genes including ACP5, CTSK, TNFRSF11A and NFATc1 under RANKL stimulation. TRAF6 and c-Src interacts with each other and with RANK upon stimulation with RANKL. This interaction increases the kinase activity of c-Src leading to the tyrosine phosphorylation of downstream molecules such as c-Cbl and activation of Akt/PKB which in turn requires the PI3-Kinase activity. Genetic experiments have shown that c-Src is very important in osteoclastogenesis. In addition to these pathways, aPKC/p62 signaling is also reported to be essential for osteoclastogenesis. Apart from their role in osteoclast differentiation and function, RANKL-RANK signaling is also required for development of lymph node and lactating mammary glands in mice and in the establishment of thymic microenvironment.

Please access this pathway at NetSlim database.

If you use this pathway, you must cite following paper: Raju, R., Balakrishnan, L., Nanjappa, V., Bhattacharjee, M., Getnet, D., Muthusamy, B., Thomas, J. K., Sharma, J., Rahiman, B. A., Harsha, H. C., Shankar, S., Prasad, T. S. K., Mohan, S. S., Bader, G. D., Wani, M. R. and Pandey, A. (2011). A comprehensive manually curated reaction map of RANKL/RANK signaling pathway. Database (Oxford). 2011, bar021.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP2018(79959) with a 97.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
90025view19:33, 8 October 2016AlexanderPicoModified description
89881view12:58, 6 October 2016MkutmonOntology Term : 'signaling pathway' added !
89880view12:58, 6 October 2016MkutmonOntology Term : 'signaling pathway pertinent to development' added !
89879view12:57, 6 October 2016MkutmonModified description
80718view15:23, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACP5RnaENSBTAG00000004826 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54
AKT1ProteinENSBTAG00000017636 (Ensembl)
  • AKT1 undergoes induced phosphorylation upon stimulation with RANKL at Thr-308 and Ser-473 in mouse bone marrow derived macrophages and in maouse macrophage cell line, RAW264.7.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
AKT2ProteinENSBTAG00000001400 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:208
BIKBAProteinENSBTAG00000016683 (Ensembl)
  • NFKBIA undergoes induced phosphorylation at Ser-32 in mouse bone marrow macrophages and in RAW264.7 cells.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
CALCRRnaENSBTAG00000017458 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:799
CBLProteinENSBTAG00000006817 (Ensembl)
  • RANKL stimulation induced the phosphorylation of CBL at Tyr-731 in mouse macrophage-like cell line, RAW264.7
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:867
CDC42ProteinENSBTAG00000001700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:998
CHUKProteinENSBTAG00000007591 (Ensembl)
  • CHUK undergoes induced phosphorylation upon stimulation with RANKL in human umbilical vein endothelial cells (HUVECs) and RAW264.7 cells
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
CTSKRnaENSBTAG00000021035 (Ensembl)
  • Type your comment here
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1513
FHL2ProteinENSBTAG00000001086 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2274
FOSProteinENSBTAG00000004322 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2353
GAB2Protein
ICAM1RnaENSBTAG00000010303 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3383
IKBKBProteinENSBTAG00000007599 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
IKBKGProteinENSBTAG00000006268 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
IP3MetaboliteHMDB01498 (HMDB)
JUNProteinENSBTAG00000004037 (Ensembl)
  • JUN undergoes induced phosphorylatin at Ser-63 and Ser-73 in mouse bone marrow derived macrophages, preosteoclasts and 293 cells. Amino acid residues 340-421 of TNFRSF11A are required for its activation
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
LYNProteinENSBTAG00000020034 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4067
MAP2K1ProteinENSBTAG00000033983 (Ensembl)
  • RANKL stimulation induces MEK1 phosphorylation in RAW264.7 cells
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5604
MAP2K6ProteinENSBTAG00000001609 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5608
MAP2K7ProteinENSBTAG00000010639 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5609
MAP3K7ProteinENSBTAG00000002625 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6885
MAP3K7IP1ProteinENSBTAG00000019828 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10454
MAPK14ProteinENSBTAG00000020783 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1432
MAPK1ProteinENSBTAG00000010312 (Ensembl)
  • MAPK1 undergoes induced phosphorylation upon RANKL stimulation in mouse macrophage cell line, RAW264.7, mouse bone marrow derived macrophages, osteoclasts and in dendritic cells.
  • Type your comment here
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3ProteinENSBTAG00000016156 (Ensembl)
  • MAPK3 undergoes induced phosphorylation upon stimulation with RANKL at Thr-202 and Tyr-204 in mouse macrophage cell line, RAW264.7, mouse bone marrow derived macrophages, osteoclasts and dendritic cells.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK8ProteinENSBTAG00000007876 (Ensembl)
  • RANKL induces MAPK8 phosphorylation at Ser 183 and Tyr-185 in mouse bone marrow macrophages and preosteoclasts
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9ProteinENSBTAG00000004709 (Ensembl)
  • RANKL induces MAPK9 phosphorylation at Thr-183 and Tyr-185 in mouse bone marrow derived macrophages.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
MITFProteinENSBTAG00000006679 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4286
MTORProteinENSBTAG00000015325 (Ensembl)
  • MTOR undergoes autophosphorylation upon stimulation with RANKL in osteoclasts and RAW264.7 murine macrophage cells.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2475
NFATC1RnaENSBTAG00000000656 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4772
NFKB1ProteinENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NFKB2ProteinENSBTAG00000006017 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4791
PAPSS2ProteinENSBTAG00000003196 (Ensembl)
  • RANKL stimulation leads to the activation of alternative NF-kappa B pathway which induced the formation of p52/RELB heterodimers through the activation of MAP3K14 (NIK). NIK deficient mice impairs RANKL mediated osteoclastogenesis.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9060
PIK3R1ProteinENSBTAG00000010989 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
PIK3R2ProteinHomologyConvert: Multiple homologues found: En:ENSBTAG00000002350;En:ENSBTAG00000002350;
PLCG1ProteinENSBTAG00000017584 (Ensembl)
  • RANKL stimulation induces PLCG1 phosphorylation in bone marrow derived macrophages and RAW264.7 cells.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5335
PTK2ProteinENSBTAG00000009578 (Ensembl)
  • RANKL stimulation induces PTK2 phosphorylation in human umbilical vein endothelial (HUVEC) cells and RAW264.7 cells
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5747
RAC1ProteinENSBTAG00000009233 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
RELAProteinENSBTAG00000013895 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5970
RELBProteinENSBTAG00000038428 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5971
ROSMetaboliteCHEBI:26523 (ChEBI)
SPI1ProteinENSBTAG00000021709 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6688
SQSTM1ProteinENSBTAG00000015591 (Ensembl)
  • TRAF6 undergoes polyubiquitination upon stimulation with RANKL which is further enhanced by IFN-gamma in mouse macrophage cell line RAW 264.7 and in mouse bone marrow derived macrophages.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8878
SRCProteinENSBTAG00000008938 (Ensembl)
  • SRC undergoes induced phosphorylation at tyrosine residue upon stimulation with RANKL in murine bone marrow derived macrophages, pre-osteoclasts and in RAW264.7 cells.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
STAT1ProteinENSBTAG00000007867 (Ensembl)
  • RANKL stimulation induces STAT1 phosphorylation at Ser-727 in mouse pre-osteoclasts and bone marrow macrophages
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6772
SYKProteinENSBTAG00000004767 (Ensembl)
  • RANKL stimulation induces SYK phosphorylation at Tyr-323 and Tyr-352 in mouse derived bone marrow cells and RAW264.7 cells
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6850
TAB2ProteinENSBTAG00000013454 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23118
TNFRSF11ARnaENSBTAG00000007569 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8792
TNFRSF11BProteinENSBTAG00000007423 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4982
TNFSF11ProteinENSBTAG00000008924 (Ensembl)
  • RANKL self associates to form a homotrimer.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8600
TRAF1ProteinENSBTAG00000003012 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7185
TRAF2ProteinENSBTAG00000010497 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7186
TRAF3ProteinENSBTAG00000013475 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7187
TRAF5ProteinENSBTAG00000012020 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7188
TRAF6ProteinENSBTAG00000036009 (Ensembl)
  • TRAF6 undergoes polyubiquitination upon stimulation with RANKL which is further enhanced by IFN-gamma in mouse macrophage cell line RAW 264.7 and in mouse bone marrow derived macrophages.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7189
VCAM1RnaENSBTAG00000007773 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7412

Annotated Interactions

No annotated interactions
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