RHOBTB GTPase Cycle (Homo sapiens)

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12, 138, 9, 11, 162-711, 1351159, 10, 15trans-Golgi network membranecytosolendosome lumenCCNE1 CUL3 ATP RHOBTB1 CUL3 RHOBTB3:ATPCCNE1 RHOBTB3:ADPCUL3 GTP RHOBTB2:GTPVHL RHOBTB3 RHOBTB3HGS LRRC41 CDC37 RAB9B RAB9A RHOBTB3:ATP:RHOBTB3interactingproteinsLRRC41 GTPHTR7 RHOBTB2 interactingproteinsCUL3 CUL3 RHOBTB1ROCK1 PiROCK2 RAB9B ADP ROCK1 GTPROCK2 RHOBTB1:GTPRHOBTB2:GTP:RHOBTB2interactingproteinsRHOBTB1 interactingproteinsCUL3 RHOBTB1:GTP:RHOBTB1interactingproteinsRHOBTB2GTP HSP90AB1 H2ORAB9A RHOBTB3 RHOBTB3 GTP HTR7 RHOBTB1 PLIN3 RHOBTB2 GTP RHOBTB3 interactingproteinsHSP90:CDC37ATP PLIN3 RHOBTB2 ATPVHL HGS HSP90AA1 1, 14


Description

RHO BTB family belongs to atypical RHO GTPases, which are characterized by the absence of GTPase activity. RhoBTB family includes RHOBTB1, RHOBTB2, and the more divergent RHOBTB3. RHOBTB1 is a component of a signaling cascade that regulates vascular function and blood pressure (Ji and Rivero 2016). RHOBTB2 is involved in COP9 signalosome-regulated and CUL3-dependent protein ubiquitination (Berthold et al. 2008; Ji and Rivero 2016). RHOBTB3 participates in CUL3 dependent protein ubiquitination, vesicle transport, regulation of the cell cycle and modulating the adaptive response to hypoxia (Berthold et al. 2008; Ji and Rivero 2016). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 9706574
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  1. Sreeramulu S, Jonker HR, Langer T, Richter C, Lancaster CR, Schwalbe H.; ''The human Cdc37.Hsp90 complex studied by heteronuclear NMR spectroscopy.''; PubMed Europe PMC Scholia
  2. Lu A, Pfeffer SR.; ''Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation and promotes cell cycle progression.''; PubMed Europe PMC Scholia
  3. Pridgeon JW, Webber EA, Sha D, Li L, Chin LS.; ''Proteomic analysis reveals Hrs ubiquitin-interacting motif-mediated ubiquitin signaling in multiple cellular processes.''; PubMed Europe PMC Scholia
  4. Matthys A, Van Craenenbroeck K, Lintermans B, Haegeman G, Vanhoenacker P.; ''RhoBTB3 interacts with the 5-HT7a receptor and inhibits its proteasomal degradation.''; PubMed Europe PMC Scholia
  5. Espinosa EJ, Calero M, Sridevi K, Pfeffer SR.; ''RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport.''; PubMed Europe PMC Scholia
  6. Schenková K, Lutz J, Kopp M, Ramos S, Rivero F.; ''MUF1/leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent cullin 3 ubiquitin ligase complexes, is a predominantly nuclear dimeric protein.''; PubMed Europe PMC Scholia
  7. Zhang CS, Liu Q, Li M, Lin SY, Peng Y, Wu D, Li TY, Fu Q, Jia W, Wang X, Ma T, Zong Y, Cui J, Pu C, Lian G, Guo H, Ye Z, Lin SC.; ''RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect.''; PubMed Europe PMC Scholia
  8. Choi YM, Kim KB, Lee JH, Chun YK, An IS, An S, Bae S.; ''DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer.''; PubMed Europe PMC Scholia
  9. Berthold J, Schenková K, Ramos S, Miura Y, Furukawa M, Aspenström P, Rivero F.; ''Characterization of RhoBTB-dependent Cul3 ubiquitin ligase complexes--evidence for an autoregulatory mechanism.''; PubMed Europe PMC Scholia
  10. Haga RB, Garg R, Collu F, Borda D'Agua B, Menéndez ST, Colomba A, Fraternali F, Ridley AJ.; ''RhoBTB1 interacts with ROCKs and inhibits invasion.''; PubMed Europe PMC Scholia
  11. Manjarrez JR, Sun L, Prince T, Matts RL.; ''Hsp90-dependent assembly of the DBC2/RhoBTB2-Cullin3 E3-ligase complex.''; PubMed Europe PMC Scholia
  12. Berthold J, Schenkova K, Rivero F.; ''Rho GTPases of the RhoBTB subfamily and tumorigenesis.''; PubMed Europe PMC Scholia
  13. Ji W, Rivero F.; ''Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis.''; PubMed Europe PMC Scholia
  14. Vaughan CK, Gohlke U, Sobott F, Good VM, Ali MM, Prodromou C, Robinson CV, Saibil HR, Pearl LH.; ''Structure of an Hsp90-Cdc37-Cdk4 complex.''; PubMed Europe PMC Scholia
  15. Mukohda M, Fang S, Wu J, Agbor LN, Nair AR, Ibeawuchi SC, Hu C, Liu X, Lu KT, Guo DF, Davis DR, Keen HL, Quelle FW, Sigmund CD.; ''RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity.''; PubMed Europe PMC Scholia
  16. Wilkins A, Ping Q, Carpenter CL.; ''RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
115128view12:18, 27 January 2021DeSlOntology Term : 'cardiovascular system homeostasis pathway' added !
115127view12:17, 27 January 2021DeSlOntology Term : 'regulatory pathway' added !
115126view12:14, 27 January 2021DeSlOntology Term : 'signaling pathway' added !
115099view17:05, 25 January 2021ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADP MetaboliteCHEBI:456216 (ChEBI)
ATP MetaboliteCHEBI:30616 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CDC37 ProteinQ16543 (Uniprot-TrEMBL)
CUL3 ProteinQ13618 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HGS ProteinO14964 (Uniprot-TrEMBL)
HSP90:CDC37ComplexR-HSA-9693661 (Reactome)
HSP90AA1 ProteinP07900 (Uniprot-TrEMBL)
HSP90AB1 ProteinP08238 (Uniprot-TrEMBL)
HTR7 ProteinP34969-2 (Uniprot-TrEMBL)
LRRC41 ProteinQ15345 (Uniprot-TrEMBL)
PLIN3 ProteinO60664 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
RAB9A ProteinP51151 (Uniprot-TrEMBL)
RAB9B ProteinQ9NP90 (Uniprot-TrEMBL)
RHOBTB1 ProteinO94844 (Uniprot-TrEMBL)
RHOBTB1 interacting proteinsComplexR-HSA-9020314 (Reactome)
RHOBTB1:GTP:RHOBTB1

interacting

proteins
ComplexR-HSA-9020317 (Reactome)
RHOBTB1:GTPComplexR-HSA-9020318 (Reactome)
RHOBTB1ProteinO94844 (Uniprot-TrEMBL)
RHOBTB2 ProteinQ9BYZ6 (Uniprot-TrEMBL)
RHOBTB2 interacting proteinsComplexR-HSA-9020341 (Reactome)
RHOBTB2:GTP:RHOBTB2

interacting

proteins
ComplexR-HSA-9020346 (Reactome)
RHOBTB2:GTPComplexR-HSA-9020344 (Reactome)
RHOBTB2ProteinQ9BYZ6 (Uniprot-TrEMBL)
RHOBTB3 ProteinO94955 (Uniprot-TrEMBL)
RHOBTB3 interacting proteinsComplexR-HSA-9706395 (Reactome)
RHOBTB3:ADPComplexR-HSA-6814647 (Reactome)
RHOBTB3:ATP:RHOBTB3

interacting

proteins
ComplexR-HSA-9706391 (Reactome)
RHOBTB3:ATPComplexR-HSA-6814649 (Reactome)
RHOBTB3ProteinO94955 (Uniprot-TrEMBL)
ROCK1 ProteinQ13464 (Uniprot-TrEMBL)
ROCK2 ProteinO75116 (Uniprot-TrEMBL)
VHL ProteinP40337 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ATPR-HSA-9706393 (Reactome)
GTPR-HSA-9018774 (Reactome)
GTPR-HSA-9018785 (Reactome)
H2OR-HSA-9706399 (Reactome)
HSP90:CDC37mim-catalysisR-HSA-9018785 (Reactome)
PiArrowR-HSA-9706399 (Reactome)
R-HSA-9018774 (Reactome) RHOBTB1 shares 80% sequence identity with RHOBTB2, with close to 95% identity in the GTPase domain (reviewed by Ji and Rivero 2016). Based on studies in RHOBTB2 (Manjarrez et al. 2014), as well as on the primary structure of the GTPase domain, RHOBTB1 is expected to bind to GTP, but not to cycle between GTP- and GDP-bound states. There are no known RHOBTB1 GAPs.
R-HSA-9018778 (Reactome) RHOBTB1, like other members of RHOBTB family, RHOBTB2 and RHOBTB3, binds to CUL3 (cullin-3), a core component of the BTB-CUL3-RBX2 E3 ubiquitin ligase complex (Berthold et al. 2008). RHOBTB1 binds to ROCK1 and ROCK2, and ROCK-mediated phosphorylation of RHOBTB1 may regulate its association with CUL3 (Haga et al. 2019). RHOBTB1 has been proposed as a substrate adaptor for PDE5, targeting it to CUL3 complexes for ubiquitination (Mukohda et al. 2019).
R-HSA-9018785 (Reactome) RHOBTB2 binds to GTP, but does not switch between GDP- and GTP-bound states (Manjarrez et al. 2014). ATP-dependent protein folding chaperone activity of the HSP90:CDC37 complex and binding of RHOBTB2 to the HSP90:CDC37 complex enables RHOBTB2 to bind GTP (Manjarrez et al. 2014). There are no known RHOBTB2 GAPs.
R-HSA-9018787 (Reactome) RHOBTB2, like other RHOBTB family members, RHOBTB1 and RHOBTB3, binds CUL3 (cullin-3) (Berthold et al. 2008), a core component of BTB-CUL3-RBX1 E3 ubiquitin ligase complexes. Binding of GTP to RHOBTB2, facilitated by the HSP90 chaperone complex, enables binding of RHOBTB2 to CUL3 (Manjarrez et al. 2014). RHOBTB2 is thought to act as the regulatory BTB component of the BTB-CUL3-RBX1 complex by recruiting target proteins for ubiquitination and subsequent proteasome-mediated degradation (Wilkins et al. 2004). RHOBTB2 is a substrate adaptor for Musashi 2 (MSI2), targeting it to CUL3 complexes for ubiquitination and proteasomal degradation, thus suppressing tumorigenesis (Choi et al. 2017).
R-HSA-9706390 (Reactome) RHOBTB3, like other RHOBTB family members, RHOBTB1 and RHOBTB2, binds CUL3 (cullin 3) a core component of BTB:CUL3:RBX1 E3 ubiquitin ligase complexes (Berthold et al. 2008). The following proteins are substrates of RHOBTB3-dependent ubiquitin ligase complexes:
RAB9A, RAB9B (Espinosa et al. 2009)
Cyclin E1 (Lu and Pfeffer 2013)
LRRC41 (MUF1) (Schenková et al. 2012).

The following proteins bind directly to RHOBTB3 but there is no evidence that they are substrates of RHOBTB3-dependent ubiquitin ligase complexes:
HGS (HRS) (Pridgeon et al. 2009)
PLIN3 (TIP47) (Espinosa et al. 2009)
5-HT7a serotonin receptor (Matthys et al. 2012)
VHL (Zhang et al. 2015).
R-HSA-9706393 (Reactome) The GTPase domain of RHOBTB3 is considerably divergent and binds ATP instead of GTP by virtue of some critical amino acid replacements in the G4 and G5 motifs (Espinosa et al. 2009).
R-HSA-9706399 (Reactome) The GTPase domain of RHOBTB3 is considerably divergent and binds and hydrolyzes ATP instead of GTP by virtue of some critical amino acid replacements in the G4 and G5 motifs (Espinosa et al. 2009). Binding of Rab9 increases the ATPase activity (Espinosa et al. 2009).
RHOBTB1 interacting proteinsR-HSA-9018778 (Reactome)
RHOBTB1:GTP:RHOBTB1

interacting

proteins
ArrowR-HSA-9018778 (Reactome)
RHOBTB1:GTPArrowR-HSA-9018774 (Reactome)
RHOBTB1:GTPR-HSA-9018778 (Reactome)
RHOBTB1R-HSA-9018774 (Reactome)
RHOBTB2 interacting proteinsR-HSA-9018787 (Reactome)
RHOBTB2:GTP:RHOBTB2

interacting

proteins
ArrowR-HSA-9018787 (Reactome)
RHOBTB2:GTPArrowR-HSA-9018785 (Reactome)
RHOBTB2:GTPR-HSA-9018787 (Reactome)
RHOBTB2R-HSA-9018785 (Reactome)
RHOBTB3 interacting proteinsR-HSA-9706390 (Reactome)
RHOBTB3:ADPArrowR-HSA-9706399 (Reactome)
RHOBTB3:ATP:RHOBTB3

interacting

proteins
ArrowR-HSA-9706390 (Reactome)
RHOBTB3:ATPArrowR-HSA-9706393 (Reactome)
RHOBTB3:ATPR-HSA-9706390 (Reactome)
RHOBTB3:ATPR-HSA-9706399 (Reactome)
RHOBTB3:ATPmim-catalysisR-HSA-9706399 (Reactome)
RHOBTB3R-HSA-9706393 (Reactome)
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