TBC/RABGAPs (Homo sapiens)

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12, 221614, 232, 9, 17, 19161, 4, 510715, 20213, 111068, 1318cytoplasmic vesicle membraneearly endosome membranemicrovillusautophagosomeclathrin-coated vesicle membraneendoplasmic reticulum-Golgi intermediate compartment membranelysosomal membranecytosolrecycling endosomeGolgi lumenPiTBC1D2RABGAP1RAB7B RAB7A RAB6B RAB33:GTPRAB6:GTPGTP RABGAP1:RAB6:GTPRABGEF1 GGA3 RAB33:GDPRAB7:GTPTBC1D15RAB35:GTPTBC1D14 TBC1D10A:ARF6:GTPRAB33A ULK1GGA1 GGC-RAB4A:GTPRAB7A TBC1D10A GABARAP RAB8A GTP RAB11B TBC1D25 GTP RAB7A TBC1D3TBC1D25GTP OPTN:RAB8:GTP:TBC1D17RAB11A GABARAPL2 GGA2 RABEP1 RABGEF1 GGA2 TBC1D10AARF6 TBC1D14:RAB11:ULK1OPTN POLGRAB5A POLG RAB8B RAB35:GDPH2OTBC1D3 PiJFC1RAB33B TBC1D10A:JFC1RAB7A:GTPGDP TBC1D17 ARF6 RAB5B GTP RAB33B GDP TBC1D7 GGC-RAB4A RAB6B RAB35 GTP GTP RABEP1 TBC1D3:GGA:RAB5:GTP:RABGEF1TBC1D14GGA1 JFC1 TSC1 GDP TBC1D7TBC1D17OPTN MAP1LC3B GGA1,2,3:RAB5:GTP:RABGEF1H2OGTP RAB33A RAB5A RAB5C GGA3 ARF6:GTPGTP PiRAB11B RABGAP1 RAB8A GDP RAB11GTP GDP H2ORAB5C TBC1D10B ULK1 TBC1D20:POLGTBC1D24 ATG8 homologuesRAB5B TBC1D10A TBC1D10C RAB8B TSC2 RAB6A TSC1 GABARAP TBC1D20 TBC1D10A TBC1D16GABARAPL2 TBC1D13 TBC1D7:TSC1:TSC2RAB7A:GDPH2ORAB7:GDPTBC1D25:ATG8homooguesRAB11A GGC-RAB4A RAB35 specific TBCRabGAPsRAB35 GTP RAB7A GTP MAP1LC3B PiTSC1:TSC2RAB7B GGC-RAB4A:GDPTSC2 RAB6A OPTN:RAB8:GTPTBC1D20PiGTP H2O


Description

Rab GTPases are peripheral membrane proteins involved in membrane trafficking. Often through their indirect interactions with coat components, motors, tethering factors and SNAREs, the Rab GTPases serve as multifaceted organizers of almost all membrane trafficking processes in eukaryotic cells. To perform these diverse processes, Rab GTPases interconvert between an active GTP-bound form and an inactive, GDP-bound form. The GTP-bound activated form mediates membrane transport through specific interaction with multiple effector molecules (Zerial & McBride 2001, Stenmark 2009, Zhen & Stenmark 2015, Cherfils & Zeghouf 2013). Conversion from the GTP- to the GDP-bound form occurs through GTP hydrolysis, which is not only driven by the intrinsic GTPase activity of the Rab protein but is also catalysed by GTPase-activating proteins (GAPs). GAPs not only increase the rate of GTP hydrolysis, but they are also involved in the inactivation of RABs, making sure they are inactivated at the correct membrane. Human cells contain as many as 70 Rabs and at least 51 putative Rab GAPs (Pfeffer 2005). Only a few of these GAPs have been matched to a specific Rab substrate. The Tre-2/Bub2/Cdc16 (TBC) domain-containing RAB-specific GAPs (TBC/RABGAPs) are a key family of RAB regulators, where the TBC domain facilitates the inactivation of RABs by facilitating activation of GTPase activity of the RAB (Pan et al. 2006, Frasa et al. 2012, Stenmark 2009). Studies suggest that TBC/RABGAPs are more than just negative regulators of RABs and can integrate signalling between RABs and other small GTPases, thereby regulating numerous cellular processes like intracellular trafficking (Frasa et al. 2012). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8854214
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Garapati, Phani Vijay

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Bibliography

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  1. Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Grønborg M, Möbius W, Rhee J, Barr FA, Simons M.; ''Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C.''; PubMed Europe PMC
  2. Huang J, Manning BD.; ''The TSC1-TSC2 complex: a molecular switchboard controlling cell growth.''; PubMed Europe PMC
  3. Peralta ER, Martin BC, Edinger AL.; ''Differential effects of TBC1D15 and mammalian Vps39 on Rab7 activation state, lysosomal morphology, and growth factor dependence.''; PubMed Europe PMC
  4. Uytterhoeven V, Kuenen S, Kasprowicz J, Miskiewicz K, Verstreken P.; ''Loss of skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins.''; PubMed Europe PMC
  5. Davey JR, Humphrey SJ, Junutula JR, Mishra AK, Lambright DG, James DE, Stöckli J.; ''TBC1D13 is a RAB35 specific GAP that plays an important role in GLUT4 trafficking in adipocytes.''; PubMed Europe PMC
  6. Vaibhava V, Nagabhushana A, Chalasani ML, Sudhakar C, Kumari A, Swarup G.; ''Optineurin mediates a negative regulation of Rab8 by the GTPase-activating protein TBC1D17.''; PubMed Europe PMC
  7. Longatti A, Lamb CA, Razi M, Yoshimura S, Barr FA, Tooze SA.; ''TBC1D14 regulates autophagosome formation via Rab11- and ULK1-positive recycling endosomes.''; PubMed Europe PMC
  8. Frittoli E, Palamidessi A, Pizzigoni A, Lanzetti L, Garrè M, Troglio F, Troilo A, Fukuda M, Di Fiore PP, Scita G, Confalonieri S.; ''The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway.''; PubMed Europe PMC
  9. Nakashima A, Yoshino K, Miyamoto T, Eguchi S, Oshiro N, Kikkawa U, Yonezawa K.; ''Identification of TBC7 having TBC domain as a novel binding protein to TSC1-TSC2 complex.''; PubMed Europe PMC
  10. Hokanson DE, Bretscher AP.; ''EPI64 interacts with Slp1/JFC1 to coordinate Rab8a and Arf6 membrane trafficking.''; PubMed Europe PMC
  11. Zhang XM, Walsh B, Mitchell CA, Rowe T.; ''TBC domain family, member 15 is a novel mammalian Rab GTPase-activating protein with substrate preference for Rab7.''; PubMed Europe PMC
  12. Frasa MA, Koessmeier KT, Ahmadian MR, Braga VM.; ''Illuminating the functional and structural repertoire of human TBC/RABGAPs.''; PubMed Europe PMC
  13. Wainszelbaum MJ, Charron AJ, Kong C, Kirkpatrick DS, Srikanth P, Barbieri MA, Gygi SP, Stahl PD.; ''The hominoid-specific oncogene TBC1D3 activates Ras and modulates epidermal growth factor receptor signaling and trafficking.''; PubMed Europe PMC
  14. Carroll B, Mohd-Naim N, Maximiano F, Frasa MA, McCormack J, Finelli M, Thoresen SB, Perdios L, Daigaku R, Francis RE, Futter C, Dikic I, Braga VM.; ''The TBC/RabGAP Armus coordinates Rac1 and Rab7 functions during autophagy.''; PubMed Europe PMC
  15. Miserey-Lenkei S, Couëdel-Courteille A, Del Nery E, Bardin S, Piel M, Racine V, Sibarita JB, Perez F, Bornens M, Goud B.; ''A role for the Rab6A' GTPase in the inactivation of the Mad2-spindle checkpoint.''; PubMed Europe PMC
  16. Itoh T, Kanno E, Uemura T, Waguri S, Fukuda M.; ''OATL1, a novel autophagosome-resident Rab33B-GAP, regulates autophagosomal maturation.''; PubMed Europe PMC
  17. Sato N, Koinuma J, Ito T, Tsuchiya E, Kondo S, Nakamura Y, Daigo Y.; ''Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis.''; PubMed Europe PMC
  18. Goueli BS, Powell MB, Finger EC, Pfeffer SR.; ''TBC1D16 is a Rab4A GTPase activating protein that regulates receptor recycling and EGF receptor signaling.''; PubMed Europe PMC
  19. Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD.; ''TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1.''; PubMed Europe PMC
  20. Cuif MH, Possmayer F, Zander H, Bordes N, Jollivet F, Couedel-Courteille A, Janoueix-Lerosey I, Langsley G, Bornens M, Goud B.; ''Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome.''; PubMed Europe PMC
  21. Sklan EH, Serrano RL, Einav S, Pfeffer SR, Lambright DG, Glenn JS.; ''TBC1D20 is a Rab1 GTPase-activating protein that mediates hepatitis C virus replication.''; PubMed Europe PMC
  22. Pan X, Eathiraj S, Munson M, Lambright DG.; ''TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism.''; PubMed Europe PMC
  23. Frasa MA, Maximiano FC, Smolarczyk K, Francis RE, Betson ME, Lozano E, Goldenring J, Seabra MC, Rak A, Ahmadian MR, Braga VM.; ''Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101572view11:44, 1 November 2018ReactomeTeamreactome version 66
101108view21:27, 31 October 2018ReactomeTeamreactome version 65
100637view20:01, 31 October 2018ReactomeTeamreactome version 64
100187view16:46, 31 October 2018ReactomeTeamreactome version 63
99737view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99304view12:46, 31 October 2018ReactomeTeamreactome version 62
93326view11:20, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ARF6 ProteinP62330 (Uniprot-TrEMBL)
ARF6:GTPComplexR-HSA-2193115 (Reactome)
ATG8 homologuesComplexR-HSA-8854613 (Reactome)
GABARAP ProteinO95166 (Uniprot-TrEMBL)
GABARAPL2 ProteinP60520 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GGA1 ProteinQ9UJY5 (Uniprot-TrEMBL)
GGA1,2,3:RAB5:GTP:RABGEF1ComplexR-HSA-8854250 (Reactome)
GGA2 ProteinQ9UJY4 (Uniprot-TrEMBL)
GGA3 ProteinQ9NZ52 (Uniprot-TrEMBL)
GGC-RAB4A ProteinP20338 (Uniprot-TrEMBL)
GGC-RAB4A:GDPComplexR-HSA-8854611 (Reactome)
GGC-RAB4A:GTPComplexR-HSA-1458538 (Reactome)
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
JFC1 ProteinQ8IYJ3 (Uniprot-TrEMBL)
JFC1ProteinQ8IYJ3 (Uniprot-TrEMBL)
MAP1LC3B ProteinQ9GZQ8 (Uniprot-TrEMBL)
OPTN ProteinQ96CV9 (Uniprot-TrEMBL)
OPTN:RAB8:GTP:TBC1D17ComplexR-HSA-8854298 (Reactome)
OPTN:RAB8:GTPComplexR-HSA-8854278 (Reactome)
POLG ProteinP27958 (Uniprot-TrEMBL)
POLGProteinP27958 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RAB11A ProteinP62491 (Uniprot-TrEMBL)
RAB11B ProteinQ15907 (Uniprot-TrEMBL)
RAB11ComplexR-HSA-8854758 (Reactome)
RAB33:GDPComplexR-HSA-8854591 (Reactome)
RAB33:GTPComplexR-HSA-8854602 (Reactome)
RAB33A ProteinQ14088 (Uniprot-TrEMBL)
RAB33B ProteinQ9H082 (Uniprot-TrEMBL)
RAB35 ProteinQ15286 (Uniprot-TrEMBL)
RAB35 specific TBC RabGAPsComplexR-HSA-8854234 (Reactome)
RAB35:GDPComplexR-HSA-8854215 (Reactome)
RAB35:GTPComplexR-HSA-8854335 (Reactome)
RAB5A ProteinP20339 (Uniprot-TrEMBL)
RAB5B ProteinP61020 (Uniprot-TrEMBL)
RAB5C ProteinP51148 (Uniprot-TrEMBL)
RAB6:GTPComplexR-HSA-8849251 (Reactome)
RAB6A ProteinP20340 (Uniprot-TrEMBL)
RAB6B ProteinQ9NRW1 (Uniprot-TrEMBL)
RAB7:GDPComplexR-HSA-8854216 (Reactome)
RAB7:GTPComplexR-HSA-8854204 (Reactome)
RAB7A ProteinP51149 (Uniprot-TrEMBL)
RAB7A:GDPComplexR-HSA-8854176 (Reactome)
RAB7A:GTPComplexR-HSA-2213222 (Reactome)
RAB7B ProteinQ96AH8 (Uniprot-TrEMBL)
RAB8A ProteinP61006 (Uniprot-TrEMBL)
RAB8B ProteinQ92930 (Uniprot-TrEMBL)
RABEP1 ProteinQ15276 (Uniprot-TrEMBL)
RABGAP1 ProteinQ9Y3P9 (Uniprot-TrEMBL)
RABGAP1:RAB6:GTPComplexR-HSA-8854244 (Reactome)
RABGAP1ProteinQ9Y3P9 (Uniprot-TrEMBL)
RABGEF1 ProteinQ9UJ41 (Uniprot-TrEMBL)
TBC1D10A ProteinQ9BXI6 (Uniprot-TrEMBL)
TBC1D10A:ARF6:GTPComplexR-HSA-8854243 (Reactome)
TBC1D10A:JFC1ComplexR-HSA-8854175 (Reactome)
TBC1D10AProteinQ9BXI6 (Uniprot-TrEMBL)
TBC1D10B ProteinQ4KMP7 (Uniprot-TrEMBL)
TBC1D10C ProteinQ8IV04 (Uniprot-TrEMBL)
TBC1D13 ProteinQ9NVG8 (Uniprot-TrEMBL)
TBC1D14 ProteinQ9P2M4 (Uniprot-TrEMBL)
TBC1D14:RAB11:ULK1ComplexR-HSA-8854760 (Reactome)
TBC1D14ProteinQ9P2M4 (Uniprot-TrEMBL)
TBC1D15ProteinQ8TC07 (Uniprot-TrEMBL)
TBC1D16ProteinQ8TBP0 (Uniprot-TrEMBL)
TBC1D17 ProteinQ9HA65 (Uniprot-TrEMBL)
TBC1D17ProteinQ9HA65 (Uniprot-TrEMBL)
TBC1D20 ProteinQ96BZ9 (Uniprot-TrEMBL)
TBC1D20:POLGComplexR-HSA-8854221 (Reactome)
TBC1D20ProteinQ96BZ9 (Uniprot-TrEMBL)
TBC1D24 ProteinQ9ULP9 (Uniprot-TrEMBL)
TBC1D25 ProteinQ3MII6 (Uniprot-TrEMBL)
TBC1D25:ATG8 homooguesComplexR-HSA-8854597 (Reactome)
TBC1D25ProteinQ3MII6 (Uniprot-TrEMBL)
TBC1D2ProteinQ9BYX2 (Uniprot-TrEMBL)
TBC1D3 ProteinQ8IZP1 (Uniprot-TrEMBL)
TBC1D3:GGA:RAB5:GTP:RABGEF1ComplexR-HSA-8854206 (Reactome)
TBC1D3ProteinQ8IZP1 (Uniprot-TrEMBL)
TBC1D7 ProteinQ9P0N9 (Uniprot-TrEMBL)
TBC1D7:TSC1:TSC2ComplexR-HSA-8854324 (Reactome)
TBC1D7ProteinQ9P0N9 (Uniprot-TrEMBL)
TSC1 ProteinQ92574 (Uniprot-TrEMBL)
TSC1:TSC2ComplexR-HSA-165175 (Reactome)
TSC2 ProteinP49815 (Uniprot-TrEMBL)
ULK1 ProteinO75385 (Uniprot-TrEMBL)
ULK1ProteinO75385 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ARF6:GTPR-HSA-8854293 (Reactome)
ATG8 homologuesR-HSA-8854588 (Reactome)
GGA1,2,3:RAB5:GTP:RABGEF1R-HSA-8854222 (Reactome)
GGC-RAB4A:GDPArrowR-HSA-8854604 (Reactome)
GGC-RAB4A:GTPR-HSA-8854604 (Reactome)
GGC-RAB4A:GTPmim-catalysisR-HSA-8854604 (Reactome)
H2OR-HSA-8854173 (Reactome)
H2OR-HSA-8854255 (Reactome)
H2OR-HSA-8854329 (Reactome)
H2OR-HSA-8854604 (Reactome)
H2OR-HSA-8854612 (Reactome)
JFC1R-HSA-8854209 (Reactome)
OPTN:RAB8:GTP:TBC1D17ArrowR-HSA-8854182 (Reactome)
OPTN:RAB8:GTPR-HSA-8854182 (Reactome)
POLGR-HSA-8854290 (Reactome)
PiArrowR-HSA-8854173 (Reactome)
PiArrowR-HSA-8854255 (Reactome)
PiArrowR-HSA-8854329 (Reactome)
PiArrowR-HSA-8854604 (Reactome)
PiArrowR-HSA-8854612 (Reactome)
R-HSA-8854173 (Reactome) RAB35 is a Rab protein with both plasma membrane and endosomal membrane localization, where it controls vesicular trafficking. RAB35 regulates the endocytic recycling of numerous protein cargoes, is involved in the recycling of synaptic vesicles (Uytterhoeven et al. 2011; Allaire et al. 2010, Sato et al. 2008, Sheehan et al. 2106, Klinkert & Echard 2016), controls the fusion of exosomes (Hsu et al. 2010), and regulates the actin cytoskeleton (Zhang et al. 2009). At least five different members of the TBC protein family are GAPs for Rab35. The three members of TBC1D10A-C family (also known as EPI64A-C) are identified to have Rab35-specific GAP activity and regulate exosome secretion (Hsu et al. 2010). TBC1D10 family members are also involved in the endocytic recycling and prevent cytokinesis (Kouranti et al. 2006, Chesneau et al. 2012).
TBC1D13 was identified as a specific GAP for Rab35 and observed to act as a potent inhibitor of insulin-stimulated GLUT4 translocation (Davey et al. 2012). TBC1D24 is a homolog of a Drosophila protein called skywalker, which has been shown to exhibit GAP activity towards Rab35 (Uytterhoeven et al. 2011).
R-HSA-8854182 (Reactome) Rab8 is a small GTPase that is specifically involved in the regulation of secretory/recycling vesicles, modulation of the actin cytoskeleton, and cell polarity. TBC (Tre2/Bub2/Cdc16) domain family member 17 (TAB1CD17), a member of the Rab GTPase-activating protein, regulates Rab8-mediated endocytic trafficking of transferrin receptor through its interaction with optineurin (OPTN) (Vaibhava et al. 2012).
R-HSA-8854209 (Reactome) TBC1D10A (EPI64) stabilizes active ARF6 and also has an additional function in the ARF6-dependent pathway through regulating the levels of active RAB8A. RAB8A is involved in the recycling pathway from endosomes back to the plasma membrane. TBC1D10A binds the Rab8a effector JFC1 and reduces the level of Rab8a:GTP to regulate Rab8a/Arf6-dependent membrane trafficking. TBC1D10A binds JFC1 through its (Slp) homology domain (SHD), and JFC1 can simultaneously interact with active Rab8a (Hokanson & Bretscher 2011).
R-HSA-8854222 (Reactome) TBC1 domain family member 3 (TBC1D3) belongs to the TBC/RabGAPs family and contains a TBC (Tre-2/Bub2/Cdc16) domain but has no GAP activity. It regulates macropinocytosis in response to epidermal growth factor (EGF), and facilitates crosstalk between the GTPases ARF6 and RAB5 (Frittoli et al. 2008). TBC1D3 binds to the ARF6 effector protein GGA (Golgi-localized, gamma-ear-containing, ARF-binding protein), which binds to a complex consisting of the RAB5GEF, rabaptin 5-associated exchange factor for Rab5 (RABEX5), and the Rab5 effector Rabaptin-5, thereby providing an indirect interaction between TBC1D3 and RAB5. Although TBC1D3 associates with Rab5, it may operate as a Rab5 effector, and not as a Rab5 GAP (Huaiping et al. 2007, Wainszelbaum et al. 2008).
R-HSA-8854255 (Reactome) RAB7, a small GTPase of the Rab family is associated with both endosomes and lysosomes. It facilitates endosomal maturation, transport from late endosomes to lysosomes, and the positioning of endosomes and lysosomes via regulating their movement along the cytoskeleton. RAB7 is inactivated through hydrolysis of bound GTP into GDP by its intrinsic GTPase activity, which is catalysed by the activity of a GAP (GTPase activating protein).
TBC1 domain family member 2A (TBC1D2A also referred as ARMUS for variant c; PARIS1 for variant a) is a member of the TBC/RabGAP family (Tre2/Bub2/Cdc16; TBC domain) that specifically inactivates RAB7 by accelerating its GTPase activity. TBC1D2A binds specifically to activated Rac1 and its C-terminal TBC/RabGAP domain inactivates RAB7 to promote ARF6-induced E-Cadherin degradation (Frasa et al. 2010). During the regulation of autophagy, TBC1D2A is recruited to autophagosomes by interacting with LC3, a core autophagy regulator, thereby inhibiting RAB7 (Carroll et al. 2013)
R-HSA-8854290 (Reactome) TBC (Tre2/Bub2/Cdc16) domain family member 20 (TBC1D20), is a member of the Rab GAP for Rab1, the Rab involved in the regulation of ER-to-Golgi transport. TBC1D20 also interacts with Hepatitis C virus (HCV) nonstructural protein NS5A and this interaction is necessary for efficient HCV infection. It has been proposed that the TBC1D20:NS5A interaction locally inactivates Rab1 at sites of nascent viral protein synthesis to promote redirection from a Golgi-bound pathway to the virus-induced membrane structures, supporting HCV RNA replication (Sklan et al. 2007).
R-HSA-8854293 (Reactome) TBC1D10A (EPI64), a RabGAP protein with a Tre-2/Bub2/Cdc16 (TBC) domain, is an effector of ARF6 and regulates ARF6-dependent membrane trafficking (Hanono et al. 2006). The TBC domain of EPI64 binds to ARF6 and stabilizes ARF6:GTP levels in a manner that is independent of its GAP activity. This interaction keeps ARF6 in an active state either by locking ARF6:GTP in an active state or may sterically hinders ARF6 from associating with its GAP, delaying the hydrolysis of bound GTP to GDP (Hokanson & Bretscher 2011).

R-HSA-8854302 (Reactome) TBC1D7 (TBC1 domain family, member 7) is a TBC (Tre-2/Bub2/Cdc16) 1 domain protein. Though TBC domain not only acts as a putative GTPase-activating protein (GAP) for small GTPases like Rab, it also have important role in cell cycle regulation and/or oncogenesis. The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex that senses specific cellular conditions to control rapamycin (mTOR) complex 1 (mTORC1) signalling. TBC1D7 stably binds to TSC1 to form the third core subunit of TSC1-TSC2 complex. The TSC1-TSC2-TBC1D7 interaction helps stabilise these three proteins in the Rhebulator complex (Nakashima et al. 2007, Dibble et al. 2012). This TSC1-TSC2 complex acts as a GAP for the small G-protein RHEB, accelerating its conversion from its active GTP-bound state to its inactive GDP-form (Huang & Manning 2008). The active RHEB is required for activation of the mTORC1, a key promoter of cell growth. In poor growth conditions, the TSC1-TSC2 complex is activated to down-regulate TORC1 activity, whereas in response to growth factors, the TSC1-TSC2 complex is inactivated to allow RHEB-GTP-dependent stimulation of growth.
R-HSA-8854303 (Reactome) Rab6 is associated with Golgi and trans-Golgi (TGN) membranes in interphase and regulates a retrograde transport route connecting early endosomes to the endoplasmic reticulum (ER). TBC domain family, member 11 (TBC1D11 also referred as GAPCENA is a Rab GTPase and directly binds Rab6 via its N-terminal PTB domain (Cuif et al. 1999, Miserey-Lenkei et al. 2006).
R-HSA-8854329 (Reactome) The small GTPase Rab7 promotes fusion events between late endosomes and lysosomes. TBC domain family, member 15 (TAB1CD15) is ubiquitously expressed and localized predominantly to the cytosol. TBC1D15 stimulates the intrinsic GTPase activity of Rab7, reducing Rab7 binding to its effector protein RILP, fragmenting the lysosome, and conferring resistance to growth factor withdrawal-induced cell death (Zhang et al. 2005, Peralta et al. 2010).
R-HSA-8854588 (Reactome) TBC (Tre2/Bub2/Cdc16) domain family member 25 (TBC1D25 also referred as OATL1), a putative GTPase activating protein (GAP), is recruited to autophagosomes through an interaction with ATG8 homologues (LC3, GABARAP and GATE-16), and is involved in the fusion between autophagosomes and lysosomes through its GAP activity. OATL1 delays autophagosomal maturation by inhibiting the encounter between autophagosomes and lysosomes (Itoh et al. 2011).
R-HSA-8854604 (Reactome) RAB4A is a master regulator of receptor recycling from endocytic compartments to the plasma membrane. It is involved in transferrin receptor recycling and EGFR trafficking and signalling. TBC (Tre2/Bub2/Cdc16) domain family member 16 (TBC1D16), is a GTPase activating protein for Rab4A and enhances the intrinsic rate of GTP hydrolysis by RAB4A (Goueli et al. 2012).
R-HSA-8854612 (Reactome) RAB33B a medial Golgi-resident Rab involved in retrograde transport, is a target of TBC1D25 (OATL1). TBC1D25 significantly accelerates the GTP hydrolysis activity of RAB33B in a dose-dependent manner (Itoh et al. 2011).
R-HSA-8854759 (Reactome) TBC (Tre2/Bub2/Cdc16) domain family, member 14 (TBC1D14) is a putative Rab GTPase activating protein (GAP) member that binds to activated Rab11 and regulates starvation-induced autophagy. TBC1D14 does not have the GAP activity and may function as Rab11 effector. TBC1D14 also colocalizes and interacts with the autophagy kinase ULK1. Overexpression of TBC1D14 causes tubulation of recycling endosomes (REs), accumulation of the ULK1 complex and Rab11 on REs, and inhibition of vesicular transport from the RE (Longatti et al. 2012).
RAB11R-HSA-8854759 (Reactome)
RAB33:GDPArrowR-HSA-8854612 (Reactome)
RAB33:GTPR-HSA-8854612 (Reactome)
RAB33:GTPmim-catalysisR-HSA-8854612 (Reactome)
RAB35 specific TBC RabGAPsArrowR-HSA-8854173 (Reactome)
RAB35:GDPArrowR-HSA-8854173 (Reactome)
RAB35:GTPR-HSA-8854173 (Reactome)
RAB35:GTPmim-catalysisR-HSA-8854173 (Reactome)
RAB6:GTPR-HSA-8854303 (Reactome)
RAB7:GDPArrowR-HSA-8854329 (Reactome)
RAB7:GTPR-HSA-8854329 (Reactome)
RAB7:GTPmim-catalysisR-HSA-8854329 (Reactome)
RAB7A:GDPArrowR-HSA-8854255 (Reactome)
RAB7A:GTPR-HSA-8854255 (Reactome)
RAB7A:GTPmim-catalysisR-HSA-8854255 (Reactome)
RABGAP1:RAB6:GTPArrowR-HSA-8854303 (Reactome)
RABGAP1R-HSA-8854303 (Reactome)
TBC1D10A:ARF6:GTPArrowR-HSA-8854293 (Reactome)
TBC1D10A:JFC1ArrowR-HSA-8854209 (Reactome)
TBC1D10AR-HSA-8854209 (Reactome)
TBC1D10AR-HSA-8854293 (Reactome)
TBC1D14:RAB11:ULK1ArrowR-HSA-8854759 (Reactome)
TBC1D14R-HSA-8854759 (Reactome)
TBC1D15ArrowR-HSA-8854329 (Reactome)
TBC1D16ArrowR-HSA-8854604 (Reactome)
TBC1D17R-HSA-8854182 (Reactome)
TBC1D20:POLGArrowR-HSA-8854290 (Reactome)
TBC1D20R-HSA-8854290 (Reactome)
TBC1D25:ATG8 homooguesArrowR-HSA-8854588 (Reactome)
TBC1D25ArrowR-HSA-8854612 (Reactome)
TBC1D25R-HSA-8854588 (Reactome)
TBC1D2ArrowR-HSA-8854255 (Reactome)
TBC1D3:GGA:RAB5:GTP:RABGEF1ArrowR-HSA-8854222 (Reactome)
TBC1D3R-HSA-8854222 (Reactome)
TBC1D7:TSC1:TSC2ArrowR-HSA-8854302 (Reactome)
TBC1D7R-HSA-8854302 (Reactome)
TSC1:TSC2R-HSA-8854302 (Reactome)
ULK1R-HSA-8854759 (Reactome)
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