RAB GEFs exchange GTP for GDP on RABs (Homo sapiens)

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5, 6, 23, 71, 87...6, 16, 17, 24, 26...2, 45, 51, 108, 112...6, 8, 34, 59, 62...36, 50, 991, 6, 21, 54, 59...6, 27, 35, 76, 80...22, 37, 39, 45, 84...57, 64, 77, 113, 132...1, 3, 6, 32, 42...45, 83, 121, 154, 179...4, 7, 25, 65, 73...6, 18, 19, 30, 38...6, 9, 29, 49, 60...6, 15, 28, 43, 45...6, 31, 40, 45, 50...6, 22, 39, 45, 72...6, 13, 41, 45, 68...6, 10, 11, 45, 47...36, 50, 996, 33, 45, 46, 78...6, 12, 14, 20, 25...melanosome membranelysosomal membranecytosolrecycling endosome membranetrans-Golgi network membranecytoplasmic vesicle membranesecretory granule membraneearly endosome membranetransport vesicle membraneendoplasmic reticulum membraneGolgi membraneYWHAE GGC-RAB31 DENND2A p-S472,S490-DENND3GDI1 GDI2 p-T180,S317,S467,S556,S638,T575-ULK1DENND2C p-2S DENND1B GDI1 RGP1 CHM GDP GDI1 DENND4C GDPGDI2 RAB31 GEFsGDI2 CHML TRAPPC2L GGC-RAB9B GGC-RAB18:GDP:GDIs,CHMsGGC-RAB7:GTPDENND1B GTP GTP GGC-RAB5C GDI2 GDP GGC-RAB1A GGC-RAB6:GDP:GDIs,CHMsGGC-RAB1A CHM GGC-RAB31:GTPGDI2 RAB32,RAB38:GDP:GDIs,CHMsGDI1 RIC1:RGP1ATPGDP GGC-RAB35:GTPYWHAE GGC-RAB12:GTPCHM GDI1 GTPGGC-RAB3A GDIs,CHMsGGC-RAB14:GDP:GDIs,CHMsCHM CHM CHML GDI1 GGC-RAB13:GDP:GDIs,CHMsGGC-RAB13:GTPGGC-RAB7B GGC-RAB18:GTPDENND1C GTP DENND3 GTPGDP SBF2 RAB35 GEFsHPS1 GGC-RAB6B GDPGGC-RAB8B GGC-RAB39:GDP:GDIs,CHMsST5 TRAPPC10 GTP DENND3GDI1 GDP GDI2 GGC-RAB39:GTPDENND6A,BRAB3IL1 GGC-RAB35:GDP:GDIs,CHMsGGC-RAB14 GGC-RAB1B GGC-RAB39A GGC-RAB5:GDP:GDIs,CHMsALS2 CHML GDI2 HPS4 GDIs,CHMsGGC-RAB18 GGC-RAB9A GGC-RAB6:GTPTRAPPC13 ADPGTP GGC-RAB3A:GTPTRAPPC8 GGC-RAB32 TRAPPC12 RIC1 GTPGDI2 p-2S-DENND1A,B:YWHAEdimerHPS1:HPS4GDI1 GDI1 GDI1 GDI2 p-S536, S538 DENND1A GGC-RAB10:GDP:GDIs,CHMsDENND6B CHM GDI2 GDI1 GGC-RAB6A CHM GDIs,CHMsGGC-RAB31 GGC-RAB21 GDPCHM DENND2D GDP CHML RAB5 GEFsGTP TRAPPC3 CHML GTP GGC-RAB8B GDI2 DENND6A GDIs,CHMsGGC-RAB14:GTPCHM p-T309,S474-AKT2 DENND5B CHM ADPGGC-RAB1B p-S536, S538 DENND1A GDP GDI2 GGC-RAB31:GDP:GDIs,CHMsRIN2 GGC-RAB7B GDI1 GGC-RAB8A GAPVD1 RAB3 GEFsGGC-RAB27A GDPDENND3GDPGGC-RAB10 GGC-RAB9A GGC-RAB8A GDI1 GDP GGC-RAB12 GDI2 CHML GGC-RAB1:GTPGDI2 GTPGTPCHML MADDGGC-RAB6A GGC-RAB10 GGC-RAB7A GGC-RAB5A GDPGTP CHML GCC-RAB12:GDP:GDIs,CHMsMADD GGC-RAB21 DENND4B GDPCHML GGC-RAB21:GDP:GDIs,CHMsGGC-RAB39B GDP GGC-RAB9B CHM TRAPPC6A CHML CHM CHM GDI2 DENND4sGGC-RAB27:GDP:GDIs,CHMsGDP DENND4A CHML GDP CHM GGC-RAB39B GDI2 CHM GGC-RAB21:GTPATPCHM GGC-RAB27B GTP GGC-RAB14 CHML GGC-RAB27A GDI1 GDI1 GTP TRAPPC2 GDI2 GGC-RAB9:GTPGDP CHML GDP GGC-RAB38 GGC-RAB18 CHM GGC-RAB1:GDP:GDIs,CHMsDENND5A,BGDI1 CHML RAB3IL1 RIN3 GTPGGC-RAB13 ST5 GGC-RAB8:GTPGDI1 GDP GDI1 GGC-RAB13 Active AKTDENND1C GDP RAB21 GEFsTRAPPC4 DENND1A MON1:CCZ1GGC-RAB27B p-2S DENND1B CHM GTP CHML CHML RAB27:GTPGTPGDI2 GDPDENND1A, DENND1BYWHAE dimerGDPTRAPPC9 GGC-RAB9:GDP:GDIs,CHMsGDI1 GDP GTP GTP SBF1 GDPGTP RAB13 GEFsRAB3GAP2 GTPGDP GGC-RAB3A:GDP:GDIs,CHMsGDI1 YWHAE GDIs,CHMsCCZ1B CHML CHML CHM RAB8 GEFsANKRD27 DENND1C GGC-RAB5C GGC-RAB38 GTPGTPp-2S DENND1B p-T308,S473-AKT1 GTPDENND1B TRAPPC6B GDI2 p-S536, S538 DENND1A GGC-RAB6B GGC-RAB5:GTPGDI1 MON1B GGC-RAB35 GGC-RAB5B GAPVD1 GGC-RAB32 GGC-RAB8:GDP:GDIs,CHMsGDPGDI2 GDI1 CHML GGC-RAB12 GDPMON1A CHML GGC-RAB3A CHM CHML GDI2 RAB3IP GTPCHML GDI1 GGC-RAB10:GTPCHM p-S472,S490-DENND3 TRAPPC5 GDPRABGEF1 CHML TRAPPCsGDIs,CHMsRINL RAB3GAP1 GDI2 TRAPPC1 GGC-RAB7:GDP:GDIs,CHMsDENND5A GTPGGC-RAB5B RAB32,RAB38:GTPGDI1 RIN3 GTPCHML GDP GGC-RAB35 GTP GGC-RAB5A p-T305,S472-AKT3 GDPCHM GDI2 CCZ1 RIN1 GTP GTP GDPALS2CL DENND1A TRAPPC11 CHM GTPp-2S DENND1A,DENND1BRAB9 GEFsRAB3GAP1:RAB3GAP2GTP GDI2 CHM GGC-RAB7A GGC-RAB39A 45


Description

Human cells have more than 60 RAB proteins that are key regulators of intracellular membrane trafficking. These small GTPases contribute to trafficking specificity by localizing to the membranes of different organelles and interacting with effectors such as sorting adaptors, tethering factors, kinases, phosphatases and tubular-vesicular cargo (reviewed in Stenmark et al, 2009; Wandinger-Ness and Zerial, 2014; Zhen and Stenmark, 2015).

RAB localization depends on a number of factors including C-terminal prenylation, the sequence of upstream hypervariable regions and what nucleotide is bound, as well as interaction with RAB-interacting proteins (Chavrier et al, 1991; Ullrich et al, 1993; Soldati et al, 1994; Farnsworth et al, 1994; Seabra, 1996; Wu et al, 2010; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014). More recently, the activity of RAB GEFs has also been implicated in regulating the localization of RAB proteins (Blumer et al, 2103; Schoebel et al, 2009; Cabrera and Ungermann, 2013; reviewed in Barr, 2013; Zhen and Stenmark, 2015)

In the active, GTP-bound form, RAB proteins are membrane-associated, while in the inactive GDP-bound form, RABs are extracted from the target membrane and exist in a soluble form in complex with GDP dissociation inhibitors (GDIs) (Ullrich et al, 1993; Soldati et al, 1994; Gavriljuk et al, 2013). Conversion between the inactive and active form relies on the activities of RAB guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) (Yoshimura et al, 2010; Wu et al, 2011; Pan et al, 2006; Frasa et al, 2012; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014; Ishida et al, 2016).

Newly synthesized RABs are bound to a RAB escort protein, CHM (also known as REP1) or CHML (REP2) (Alexandrov et al, 1994; Shen and Seabra, 1996). CHM/REP proteins are the substrate-binding component of the trimeric RAB geranylgeranyltransferase enzyme (GGTaseII) along with the two catalytic subunits RABGGTA and RABGGTB (reviewed in Gutkowska and Swiezewska, 2012; Palsuledesai and Distefano, 2015). REP proteins recruit the unmodified RAB in its GDP-bound state to the GGTase for sequential geranylgeranylation at one or two C-terminal cysteine residues (Alexandrov et al, 1994; Seabra et al 1996; Shen and Seabra, 1996; Baron and Seabra, 2008). After geranylation, CHM/REP proteins remain in complex with the geranylated RAB and escort it to its target membrane, where RAB activity is regulated by GAPs, GEFs, GDIs and membrane-bound GDI displacement factors (GDFs) (Sivars et al, 2003; reviewed in Stenmark, 2009; Wandinger-Ness and Zerial, 2014).

Unlike the RAB GAPS, which (to date) all contain a shared TBC domain, RAB GEFs are structurally diverse and range from monomeric to multisubunit complexes (reviewed in Fukuda et al, 2011; Frasa et al, 2012; Cherfils and Zeghouf, 2013; Ishida et al, 2016). While many GEFs contain one of three conserved GEF domains identified to date - the DENN (differentially expressed in normal and neoplastic cell) domain, the VPS9 domain and the SEC2 domain- other GEFs lack a conserved domain (reviewed in Ishida et al, 2016). Based on sequence conservation and subunit organization, GEFs can be grouped into 6 general classes: the DENND-containing GEFs, the VPS9-containing GEFs (both monomeric), the SEC2-containing GEFs (homodimeric), heterodimeric GEF complexes such as RIC1:RGP1, the multisubunit TRAPPC GEF, and others (reviewed in Barr and Lambright, 2010; Marat et al, 2011; Ishida et al, 2016). GEFs for many RABs have still not been identified, however. View original pathway at:Reactome.

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Pathway is converted from Reactome ID: 8876198
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Reactome version: 63
Reactome Author 
Reactome Author: Rothfels, Karen

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  88. Holz RW, Brondyk WH, Senter RA, Kuizon L, Macara IG.; ''Evidence for the involvement of Rab3A in Ca(2+)-dependent exocytosis from adrenal chromaffin cells.''; PubMed Europe PMC Scholia
  89. Wada M, Nakanishi H, Satoh A, Hirano H, Obaishi H, Matsuura Y, Takai Y.; ''Isolation and characterization of a GDP/GTP exchange protein specific for the Rab3 subfamily small G proteins.''; PubMed Europe PMC Scholia
  90. Ohbayashi N, Yatsu A, Tamura K, Fukuda M.; ''The Rab21-GEF activity of Varp, but not its Rab32/38 effector function, is required for dendrite formation in melanocytes.''; PubMed Europe PMC Scholia
  91. Pavlos NJ, Jahn R.; ''Distinct yet overlapping roles of Rab GTPases on synaptic vesicles.''; PubMed Europe PMC Scholia
  92. Kulasekaran G, Nossova N, Marat AL, Lund I, Cremer C, Ioannou MS, McPherson PS.; ''Phosphorylation-dependent Regulation of Connecdenn/DENND1 Guanine Nucleotide Exchange Factors.''; PubMed Europe PMC Scholia
  93. Dambournet D, Machicoane M, Chesneau L, Sachse M, Rocancourt M, El Marjou A, Formstecher E, Salomon R, Goud B, Echard A.; ''Rab35 GTPase and OCRL phosphatase remodel lipids and F-actin for successful cytokinesis.''; PubMed Europe PMC Scholia
  94. Fukui K, Sasaki T, Imazumi K, Matsuura Y, Nakanishi H, Takai Y.; ''Isolation and characterization of a GTPase activating protein specific for the Rab3 subfamily of small G proteins.''; PubMed Europe PMC Scholia
  95. Liu S, Storrie B.; ''Are Rab proteins the link between Golgi organization and membrane trafficking?''; PubMed Europe PMC Scholia
  96. Gronemeyer T, Wiese S, Grinhagens S, Schollenberger L, Satyagraha A, Huber LA, Meyer HE, Warscheid B, Just WW.; ''Localization of Rab proteins to peroxisomes: a proteomics and immunofluorescence study.''; PubMed Europe PMC Scholia
  97. 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 Scholia
  98. Palsuledesai CC, Distefano MD.; ''Protein prenylation: enzymes, therapeutics, and biotechnology applications.''; PubMed Europe PMC Scholia
  99. 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 Scholia
  100. Wang CW, Stromhaug PE, Shima J, Klionsky DJ.; ''The Ccz1-Mon1 protein complex is required for the late step of multiple vacuole delivery pathways.''; PubMed Europe PMC Scholia
  101. Zhang J, Fonovic M, Suyama K, Bogyo M, Scott MP.; ''Rab35 controls actin bundling by recruiting fascin as an effector protein.''; PubMed Europe PMC Scholia
  102. Rahajeng J, Giridharan SS, Cai B, Naslavsky N, Caplan S.; ''MICAL-L1 is a tubular endosomal membrane hub that connects Rab35 and Arf6 with Rab8a.''; PubMed Europe PMC Scholia
  103. Jean S, Cox S, Nassari S, Kiger AA.; ''Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion.''; PubMed Europe PMC Scholia
  104. Mahoney TR, Liu Q, Itoh T, Luo S, Hadwiger G, Vincent R, Wang ZW, Fukuda M, Nonet ML.; ''Regulation of synaptic transmission by RAB-3 and RAB-27 in Caenorhabditis elegans.''; PubMed Europe PMC Scholia
  105. Iwasaki K, Staunton J, Saifee O, Nonet M, Thomas JH.; ''aex-3 encodes a novel regulator of presynaptic activity in C. elegans.''; PubMed Europe PMC Scholia
  106. Simpson JC, Griffiths G, Wessling-Resnick M, Fransen JA, Bennett H, Jones AT.; ''A role for the small GTPase Rab21 in the early endocytic pathway.''; PubMed Europe PMC Scholia
  107. Lord C, Bhandari D, Menon S, Ghassemian M, Nycz D, Hay J, Ghosh P, Ferro-Novick S.; ''Sequential interactions with Sec23 control the direction of vesicle traffic.''; PubMed Europe PMC Scholia
  108. Miller VJ, Sharma P, Kudlyk TA, Frost L, Rofe AP, Watson IJ, Duden R, Lowe M, Lupashin VV, Ungar D.; ''Molecular insights into vesicle tethering at the Golgi by the conserved oligomeric Golgi (COG) complex and the golgin TATA element modulatory factor (TMF).''; PubMed Europe PMC Scholia
  109. Cai Y, Chin HF, Lazarova D, Menon S, Fu C, Cai H, Sclafani A, Rodgers DW, De La Cruz EM, Ferro-Novick S, Reinisch KM.; ''The structural basis for activation of the Rab Ypt1p by the TRAPP membrane-tethering complexes.''; PubMed Europe PMC Scholia
  110. Ng EL, Wang Y, Tang BL.; ''Rab22B's role in trans-Golgi network membrane dynamics.''; PubMed Europe PMC Scholia
  111. Lord C, Ferro-Novick S, Miller EA.; ''The highly conserved COPII coat complex sorts cargo from the endoplasmic reticulum and targets it to the golgi.''; PubMed Europe PMC Scholia
  112. Humphrey SJ, Yang G, Yang P, Fazakerley DJ, Stöckli J, Yang JY, James DE.; ''Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2.''; PubMed Europe PMC Scholia
  113. Kondo H, Shirakawa R, Higashi T, Kawato M, Fukuda M, Kita T, Horiuchi H.; ''Constitutive GDP/GTP exchange and secretion-dependent GTP hydrolysis activity for Rab27 in platelets.''; PubMed Europe PMC Scholia
  114. Burgo A, Proux-Gillardeaux V, Sotirakis E, Bun P, Casano A, Verraes A, Liem RK, Formstecher E, Coppey-Moisan M, Galli T.; ''A molecular network for the transport of the TI-VAMP/VAMP7 vesicles from cell center to periphery.''; PubMed Europe PMC Scholia
  115. Wang W, Sacher M, Ferro-Novick S.; ''TRAPP stimulates guanine nucleotide exchange on Ypt1p.''; PubMed Europe PMC Scholia
  116. Alexandrov K, Horiuchi H, Steele-Mortimer O, Seabra MC, Zerial M.; ''Rab escort protein-1 is a multifunctional protein that accompanies newly prenylated rab proteins to their target membranes.''; PubMed Europe PMC Scholia
  117. Bao X, Faris AE, Jang EK, Haslam RJ.; ''Molecular cloning, bacterial expression and properties of Rab31 and Rab32.''; PubMed Europe PMC Scholia
  118. Cherfils J, Zeghouf M.; ''Regulation of small GTPases by GEFs, GAPs, and GDIs.''; PubMed Europe PMC Scholia
  119. Yamasaki A, Menon S, Yu S, Barrowman J, Meerloo T, Oorschot V, Klumperman J, Satoh A, Ferro-Novick S.; ''mTrs130 is a component of a mammalian TRAPPII complex, a Rab1 GEF that binds to COPI-coated vesicles.''; PubMed Europe PMC Scholia
  120. Rodriguez-Gabin AG, Yin X, Si Q, Larocca JN.; ''Transport of mannose-6-phosphate receptors from the trans-Golgi network to endosomes requires Rab31.''; PubMed Europe PMC Scholia
  121. Nagano F, Sasaki T, Fukui K, Asakura T, Imazumi K, Takai Y.; ''Molecular cloning and characterization of the noncatalytic subunit of the Rab3 subfamily-specific GTPase-activating protein.''; PubMed Europe PMC Scholia
  122. Kajiho H, Saito K, Tsujita K, Kontani K, Araki Y, Kurosu H, Katada T.; ''RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway.''; PubMed Europe PMC Scholia
  123. Sato M, Sato K, Liou W, Pant S, Harada A, Grant BD.; ''Regulation of endocytic recycling by C. elegans Rab35 and its regulator RME-4, a coated-pit protein.''; PubMed Europe PMC Scholia
  124. Vitelli R, Santillo M, Lattero D, Chiariello M, Bifulco M, Bruni CB, Bucci C.; ''Role of the small GTPase Rab7 in the late endocytic pathway.''; PubMed Europe PMC Scholia
  125. Baron RA, Seabra MC.; ''Rab geranylgeranylation occurs preferentially via the pre-formed REP-RGGT complex and is regulated by geranylgeranyl pyrophosphate.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114830view16:33, 25 January 2021ReactomeTeamReactome version 75
113276view11:34, 2 November 2020ReactomeTeamReactome version 74
112488view15:44, 9 October 2020ReactomeTeamReactome version 73
101400view11:28, 1 November 2018ReactomeTeamreactome version 66
100938view21:04, 31 October 2018ReactomeTeamreactome version 65
100475view19:38, 31 October 2018ReactomeTeamreactome version 64
100020view16:22, 31 October 2018ReactomeTeamreactome version 63
99573view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93395view11:22, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ALS2 ProteinQ96Q42 (Uniprot-TrEMBL)
ALS2CL ProteinQ60I27 (Uniprot-TrEMBL)
ANKRD27 ProteinQ96NW4 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active AKTComplexR-HSA-202074 (Reactome)
CCZ1 ProteinP86791 (Uniprot-TrEMBL)
CCZ1B ProteinP86790 (Uniprot-TrEMBL)
CHM ProteinP24386 (Uniprot-TrEMBL)
CHML ProteinP26374 (Uniprot-TrEMBL)
DENND1A ProteinQ8TEH3 (Uniprot-TrEMBL)
DENND1A, DENND1BComplexR-HSA-8933359 (Reactome)
DENND1B ProteinQ6P3S1 (Uniprot-TrEMBL)
DENND1C ProteinQ8IV53 (Uniprot-TrEMBL)
DENND2A ProteinQ9ULE3 (Uniprot-TrEMBL)
DENND2C ProteinQ68D51 (Uniprot-TrEMBL)
DENND2D ProteinQ9H6A0 (Uniprot-TrEMBL)
DENND3 ProteinA2RUS2 (Uniprot-TrEMBL)
DENND3ProteinA2RUS2 (Uniprot-TrEMBL)
DENND3ComplexR-HSA-8876437 (Reactome)
DENND4A ProteinQ7Z401 (Uniprot-TrEMBL)
DENND4B ProteinO75064 (Uniprot-TrEMBL)
DENND4C ProteinQ5VZ89 (Uniprot-TrEMBL)
DENND4sComplexR-HSA-8876092 (Reactome)
DENND5A ProteinQ6IQ26 (Uniprot-TrEMBL)
DENND5A,BComplexR-HSA-8877802 (Reactome)
DENND5B ProteinQ6ZUT9 (Uniprot-TrEMBL)
DENND6A ProteinQ8IWF6 (Uniprot-TrEMBL)
DENND6A,BComplexR-HSA-8876608 (Reactome)
DENND6B ProteinQ8NEG7 (Uniprot-TrEMBL)
GAPVD1 ProteinQ14C86 (Uniprot-TrEMBL)
GCC-RAB12:GDP:GDIs,CHMsComplexR-HSA-8876453 (Reactome)
GDI1 ProteinP31150 (Uniprot-TrEMBL)
GDI2 ProteinP50395 (Uniprot-TrEMBL)
GDIs,CHMsComplexR-HSA-8875305 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GGC-RAB10 ProteinP61026 (Uniprot-TrEMBL)
GGC-RAB10:GDP:GDIs,CHMsComplexR-HSA-8876131 (Reactome)
GGC-RAB10:GTPComplexR-HSA-8876128 (Reactome)
GGC-RAB12 ProteinQ6IQ22 (Uniprot-TrEMBL)
GGC-RAB12:GTPComplexR-HSA-8876448 (Reactome)
GGC-RAB13 ProteinP51153 (Uniprot-TrEMBL)
GGC-RAB13:GDP:GDIs,CHMsComplexR-HSA-8876604 (Reactome)
GGC-RAB13:GTPComplexR-HSA-8876599 (Reactome)
GGC-RAB14 ProteinP61106 (Uniprot-TrEMBL)
GGC-RAB14:GDP:GDIs,CHMsComplexR-HSA-8876596 (Reactome)
GGC-RAB14:GTPComplexR-HSA-8876595 (Reactome)
GGC-RAB18 ProteinQ9NP72 (Uniprot-TrEMBL)
GGC-RAB18:GDP:GDIs,CHMsComplexR-HSA-8877994 (Reactome)
GGC-RAB18:GTPComplexR-HSA-8877989 (Reactome)
GGC-RAB1:GDP:GDIs,CHMsComplexR-HSA-8877473 (Reactome)
GGC-RAB1:GTPComplexR-HSA-8877468 (Reactome)
GGC-RAB1A ProteinP62820 (Uniprot-TrEMBL)
GGC-RAB1B ProteinQ9H0U4 (Uniprot-TrEMBL)
GGC-RAB21 ProteinQ9UL25 (Uniprot-TrEMBL)
GGC-RAB21:GDP:GDIs,CHMsComplexR-HSA-8876836 (Reactome)
GGC-RAB21:GTPComplexR-HSA-8876838 (Reactome)
GGC-RAB27:GDP:GDIs,CHMsComplexR-HSA-8877298 (Reactome)
GGC-RAB27A ProteinP51159 (Uniprot-TrEMBL)
GGC-RAB27B ProteinO00194 (Uniprot-TrEMBL)
GGC-RAB31 ProteinQ13636 (Uniprot-TrEMBL)
GGC-RAB31:GDP:GDIs,CHMsComplexR-HSA-8877287 (Reactome)
GGC-RAB31:GTPComplexR-HSA-8877284 (Reactome)
GGC-RAB32 ProteinQ13637 (Uniprot-TrEMBL)
GGC-RAB35 ProteinQ15286 (Uniprot-TrEMBL)
GGC-RAB35:GDP:GDIs,CHMsComplexR-HSA-8877604 (Reactome)
GGC-RAB35:GTPComplexR-HSA-8877601 (Reactome)
GGC-RAB38 ProteinP57729 (Uniprot-TrEMBL)
GGC-RAB39:GDP:GDIs,CHMsComplexR-HSA-8877806 (Reactome)
GGC-RAB39:GTPComplexR-HSA-8877804 (Reactome)
GGC-RAB39A ProteinQ14964 (Uniprot-TrEMBL)
GGC-RAB39B ProteinQ96DA2 (Uniprot-TrEMBL)
GGC-RAB3A ProteinP20336 (Uniprot-TrEMBL)
GGC-RAB3A:GDP:GDIs,CHMsComplexR-HSA-8875313 (Reactome)
GGC-RAB3A:GTPComplexR-HSA-8875326 (Reactome)
GGC-RAB5:GDP:GDIs,CHMsComplexR-HSA-8875330 (Reactome)
GGC-RAB5:GTPComplexR-HSA-8875316 (Reactome)
GGC-RAB5A ProteinP20339 (Uniprot-TrEMBL)
GGC-RAB5B ProteinP61020 (Uniprot-TrEMBL)
GGC-RAB5C ProteinP51148 (Uniprot-TrEMBL)
GGC-RAB6:GDP:GDIs,CHMsComplexR-HSA-8876125 (Reactome)
GGC-RAB6:GTPComplexR-HSA-8876122 (Reactome)
GGC-RAB6A ProteinP20340 (Uniprot-TrEMBL)
GGC-RAB6B ProteinQ9NRW1 (Uniprot-TrEMBL)
GGC-RAB7:GDP:GDIs,CHMsComplexR-HSA-8877449 (Reactome)
GGC-RAB7:GTPComplexR-HSA-8877453 (Reactome)
GGC-RAB7A ProteinP51149 (Uniprot-TrEMBL)
GGC-RAB7B ProteinQ96AH8 (Uniprot-TrEMBL)
GGC-RAB8:GDP:GDIs,CHMsComplexR-HSA-8876120 (Reactome)
GGC-RAB8:GTPComplexR-HSA-8876116 (Reactome)
GGC-RAB8A ProteinP61006 (Uniprot-TrEMBL)
GGC-RAB8B ProteinQ92930 (Uniprot-TrEMBL)
GGC-RAB9:GDP:GDIs,CHMsComplexR-HSA-8876113 (Reactome)
GGC-RAB9:GTPComplexR-HSA-8876110 (Reactome)
GGC-RAB9A ProteinP51151 (Uniprot-TrEMBL)
GGC-RAB9B ProteinQ9NP90 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HPS1 ProteinQ92902 (Uniprot-TrEMBL)
HPS1:HPS4ComplexR-HSA-8877746 (Reactome)
HPS4 ProteinQ9NQG7 (Uniprot-TrEMBL)
MADD ProteinQ8WXG6-3 (Uniprot-TrEMBL)
MADDProteinQ8WXG6-3 (Uniprot-TrEMBL)
MON1:CCZ1ComplexR-HSA-8877446 (Reactome)
MON1A ProteinQ86VX9 (Uniprot-TrEMBL)
MON1B ProteinQ7L1V2 (Uniprot-TrEMBL)
RAB13 GEFsComplexR-HSA-8876606 (Reactome)
RAB21 GEFsComplexR-HSA-8933368 (Reactome)
RAB27:GTPComplexR-HSA-8877303 (Reactome)
RAB3 GEFsComplexR-HSA-8877301 (Reactome)
RAB31 GEFsComplexR-HSA-8877299 (Reactome)
RAB32,RAB38:GDP:GDIs,CHMsComplexR-HSA-8877756 (Reactome)
RAB32,RAB38:GTPComplexR-HSA-8877758 (Reactome)
RAB35 GEFsComplexR-HSA-8877607 (Reactome)
RAB3GAP1 ProteinQ15042 (Uniprot-TrEMBL)
RAB3GAP1:RAB3GAP2ComplexR-HSA-8877988 (Reactome)
RAB3GAP2 ProteinQ9H2M9 (Uniprot-TrEMBL)
RAB3IL1 ProteinQ8TBN0 (Uniprot-TrEMBL)
RAB3IP ProteinQ96QF0 (Uniprot-TrEMBL)
RAB5 GEFsComplexR-HSA-8875310 (Reactome)
RAB8 GEFsComplexR-HSA-8876097 (Reactome)
RAB9 GEFsComplexR-HSA-8876094 (Reactome)
RABGEF1 ProteinQ9UJ41 (Uniprot-TrEMBL)
RGP1 ProteinQ92546 (Uniprot-TrEMBL)
RIC1 ProteinQ4ADV7 (Uniprot-TrEMBL)
RIC1:RGP1ComplexR-HSA-8847862 (Reactome)
RIN1 ProteinQ13671 (Uniprot-TrEMBL)
RIN2 ProteinQ8WYP3 (Uniprot-TrEMBL)
RIN3 ProteinQ8TB24 (Uniprot-TrEMBL)
RINL ProteinQ6ZS11 (Uniprot-TrEMBL)
SBF1 ProteinO95248 (Uniprot-TrEMBL)
SBF2 ProteinQ86WG5 (Uniprot-TrEMBL)
ST5 ProteinP78524 (Uniprot-TrEMBL)
TRAPPC1 ProteinQ9Y5R8 (Uniprot-TrEMBL)
TRAPPC10 ProteinP48553 (Uniprot-TrEMBL)
TRAPPC11 ProteinQ7Z392 (Uniprot-TrEMBL)
TRAPPC12 ProteinQ8WVT3 (Uniprot-TrEMBL)
TRAPPC13 ProteinA5PLN9 (Uniprot-TrEMBL)
TRAPPC2 ProteinP0DI81 (Uniprot-TrEMBL)
TRAPPC2L ProteinQ9UL33 (Uniprot-TrEMBL)
TRAPPC3 ProteinO43617 (Uniprot-TrEMBL)
TRAPPC4 ProteinQ9Y296 (Uniprot-TrEMBL)
TRAPPC5 ProteinQ8IUR0 (Uniprot-TrEMBL)
TRAPPC6A ProteinO75865 (Uniprot-TrEMBL)
TRAPPC6B ProteinQ86SZ2 (Uniprot-TrEMBL)
TRAPPC8 ProteinQ9Y2L5 (Uniprot-TrEMBL)
TRAPPC9 ProteinQ96Q05 (Uniprot-TrEMBL)
TRAPPCsComplexR-HSA-8933216 (Reactome)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAE dimerComplexR-HSA-194364 (Reactome)
p-2S DENND1A, DENND1BComplexR-HSA-8933377 (Reactome)
p-2S DENND1B ProteinQ6P3S1 (Uniprot-TrEMBL)
p-2S-DENND1A,B:YWHAE dimerComplexR-HSA-8933379 (Reactome)
p-S472,S490-DENND3 ProteinA2RUS2 (Uniprot-TrEMBL)
p-S472,S490-DENND3ProteinA2RUS2 (Uniprot-TrEMBL)
p-S536, S538 DENND1A ProteinQ8TEH3 (Uniprot-TrEMBL)
p-T180,S317,S467,S556,S638,T575-ULK1ProteinO75385 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8876446 (Reactome)
ADPArrowR-HSA-8933446 (Reactome)
ATPR-HSA-8876446 (Reactome)
ATPR-HSA-8933446 (Reactome)
Active AKTmim-catalysisR-HSA-8933446 (Reactome)
DENND1A, DENND1BR-HSA-8933446 (Reactome)
DENND3R-HSA-8876446 (Reactome)
DENND3mim-catalysisR-HSA-8876454 (Reactome)
DENND4smim-catalysisR-HSA-8876188 (Reactome)
DENND5A,Bmim-catalysisR-HSA-8877813 (Reactome)
DENND6A,Bmim-catalysisR-HSA-8876616 (Reactome)
GCC-RAB12:GDP:GDIs,CHMsR-HSA-8876454 (Reactome)
GDIs,CHMsArrowR-HSA-8875318 (Reactome)
GDIs,CHMsArrowR-HSA-8875320 (Reactome)
GDIs,CHMsArrowR-HSA-8876188 (Reactome)
GDIs,CHMsArrowR-HSA-8876190 (Reactome)
GDIs,CHMsArrowR-HSA-8876191 (Reactome)
GDIs,CHMsArrowR-HSA-8876193 (Reactome)
GDIs,CHMsArrowR-HSA-8876454 (Reactome)
GDIs,CHMsArrowR-HSA-8876615 (Reactome)
GDIs,CHMsArrowR-HSA-8876616 (Reactome)
GDIs,CHMsArrowR-HSA-8876837 (Reactome)
GDIs,CHMsArrowR-HSA-8877308 (Reactome)
GDIs,CHMsArrowR-HSA-8877311 (Reactome)
GDIs,CHMsArrowR-HSA-8877451 (Reactome)
GDIs,CHMsArrowR-HSA-8877475 (Reactome)
GDIs,CHMsArrowR-HSA-8877612 (Reactome)
GDIs,CHMsArrowR-HSA-8877760 (Reactome)
GDIs,CHMsArrowR-HSA-8877813 (Reactome)
GDIs,CHMsArrowR-HSA-8877998 (Reactome)
GDPArrowR-HSA-8875318 (Reactome)
GDPArrowR-HSA-8875320 (Reactome)
GDPArrowR-HSA-8876188 (Reactome)
GDPArrowR-HSA-8876190 (Reactome)
GDPArrowR-HSA-8876191 (Reactome)
GDPArrowR-HSA-8876193 (Reactome)
GDPArrowR-HSA-8876454 (Reactome)
GDPArrowR-HSA-8876615 (Reactome)
GDPArrowR-HSA-8876616 (Reactome)
GDPArrowR-HSA-8876837 (Reactome)
GDPArrowR-HSA-8877308 (Reactome)
GDPArrowR-HSA-8877311 (Reactome)
GDPArrowR-HSA-8877451 (Reactome)
GDPArrowR-HSA-8877475 (Reactome)
GDPArrowR-HSA-8877612 (Reactome)
GDPArrowR-HSA-8877760 (Reactome)
GDPArrowR-HSA-8877813 (Reactome)
GDPArrowR-HSA-8877998 (Reactome)
GGC-RAB10:GDP:GDIs,CHMsR-HSA-8876188 (Reactome)
GGC-RAB10:GTPArrowR-HSA-8876188 (Reactome)
GGC-RAB12:GTPArrowR-HSA-8876454 (Reactome)
GGC-RAB13:GDP:GDIs,CHMsR-HSA-8876615 (Reactome)
GGC-RAB13:GTPArrowR-HSA-8876615 (Reactome)
GGC-RAB14:GDP:GDIs,CHMsR-HSA-8876616 (Reactome)
GGC-RAB14:GTPArrowR-HSA-8876616 (Reactome)
GGC-RAB18:GDP:GDIs,CHMsR-HSA-8877998 (Reactome)
GGC-RAB18:GTPArrowR-HSA-8877998 (Reactome)
GGC-RAB1:GDP:GDIs,CHMsR-HSA-8877475 (Reactome)
GGC-RAB1:GTPArrowR-HSA-8877475 (Reactome)
GGC-RAB21:GDP:GDIs,CHMsR-HSA-8876837 (Reactome)
GGC-RAB21:GTPArrowR-HSA-8876837 (Reactome)
GGC-RAB27:GDP:GDIs,CHMsR-HSA-8877308 (Reactome)
GGC-RAB31:GDP:GDIs,CHMsR-HSA-8877311 (Reactome)
GGC-RAB31:GTPArrowR-HSA-8877311 (Reactome)
GGC-RAB35:GDP:GDIs,CHMsR-HSA-8877612 (Reactome)
GGC-RAB35:GTPArrowR-HSA-8877612 (Reactome)
GGC-RAB39:GDP:GDIs,CHMsR-HSA-8877813 (Reactome)
GGC-RAB39:GTPArrowR-HSA-8877813 (Reactome)
GGC-RAB3A:GDP:GDIs,CHMsR-HSA-8875318 (Reactome)
GGC-RAB3A:GTPArrowR-HSA-8875318 (Reactome)
GGC-RAB5:GDP:GDIs,CHMsR-HSA-8875320 (Reactome)
GGC-RAB5:GTPArrowR-HSA-8875320 (Reactome)
GGC-RAB6:GDP:GDIs,CHMsR-HSA-8876193 (Reactome)
GGC-RAB6:GTPArrowR-HSA-8876193 (Reactome)
GGC-RAB7:GDP:GDIs,CHMsR-HSA-8877451 (Reactome)
GGC-RAB7:GTPArrowR-HSA-8877451 (Reactome)
GGC-RAB8:GDP:GDIs,CHMsR-HSA-8876190 (Reactome)
GGC-RAB8:GTPArrowR-HSA-8876190 (Reactome)
GGC-RAB9:GDP:GDIs,CHMsR-HSA-8876191 (Reactome)
GGC-RAB9:GTPArrowR-HSA-8876191 (Reactome)
GTPR-HSA-8875318 (Reactome)
GTPR-HSA-8875320 (Reactome)
GTPR-HSA-8876188 (Reactome)
GTPR-HSA-8876190 (Reactome)
GTPR-HSA-8876191 (Reactome)
GTPR-HSA-8876193 (Reactome)
GTPR-HSA-8876454 (Reactome)
GTPR-HSA-8876615 (Reactome)
GTPR-HSA-8876616 (Reactome)
GTPR-HSA-8876837 (Reactome)
GTPR-HSA-8877308 (Reactome)
GTPR-HSA-8877311 (Reactome)
GTPR-HSA-8877451 (Reactome)
GTPR-HSA-8877475 (Reactome)
GTPR-HSA-8877612 (Reactome)
GTPR-HSA-8877760 (Reactome)
GTPR-HSA-8877813 (Reactome)
GTPR-HSA-8877998 (Reactome)
HPS1:HPS4mim-catalysisR-HSA-8877760 (Reactome)
MADDmim-catalysisR-HSA-8877308 (Reactome)
MON1:CCZ1mim-catalysisR-HSA-8877451 (Reactome)
R-HSA-8875318 (Reactome) RAB3A is involved in neurotransmitter release at the synaptic vesicle (Fischer et al, 1991; Holz et al, 1994; Geppert et al, 1994; Kapfhamer et al, 2002; reviewed in Pavlos and Jahn, 2011). RAB3A is activated at the synaptic vesicle through the guanine nucleotide exchange activity of RAB3IL1 (also known as GRAB) which promotes the exchange of GDP for GTP (Luo et al, 2001; Yoshimura et al, 2010). RAB3 family members are also activated by the DENN domain-containing GEF MADD, also known as RAB3GEP (Wada et al, 1997; Fukui et al, 1997; Iwasaki et al, 1997; Mahoney et al, 2006). Interaction of RAB3A with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB3A with GDI and CHM proteins.
R-HSA-8875320 (Reactome) RAB5 has roles at early endosomal compartments including fusion of vesicles originating from the plasma membrane with early endosomes, and is implicated in clathrin-mediated endocytosis (Chavrier et al, 1990; Bucci et al, 1992; Gorvel et al, 1991; Hoffenberg et al, 2000; Zeigerer et al, 2012; Taylor et al, 2011). RAB5 activation is mediated by a number of GEFs including members of the RIN (RAS and RAB interactor) and ALS2 families and GAPVD1, all of which belong to the VPS9-domain containing group (Horiuchi et al, 1997; Tall et al, 2001; Saito et al, 2002; Kajiho et al, 2003; Kajiho et al, 2011; Kunita et al, 2004; Hadano et al, 2004; Hunker et al, 2006; Suzuki-Utsunomiya et al, 2007; reviewed in Ishida et al, 2016). Interaction of RAB5 with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB5 with GDI and CHM proteins.
R-HSA-8876188 (Reactome) RAB10 has well characterized roles in basolateral sorting and GLUT4 transport and has more recently been shown to contribute to ER dynamics and morphology (Chen et al, 1993; Babbey et al, 2006; Schuck et al, 2007; Sano et al, 2008; Chen et al, 2012; Chen and Lippincott-Schwarz, 2013; English and Voeltz, 2013). In vitro, DENN4 family members A, B and C show RAB10-specific GEF activity, and DENN4B staining colocalizes with that of RAB10 in HeLa cells (Yoshimura et al, 2010). Consistent with this, coexpression of DENND4C and RAB10 in HEK293 cells increases the fraction of GTP-bound RAB10, and DENND4C knockdown in insulin-stimulated 3T3 cells reduces the trafficking of GLUT4 to the plasma membrane (Sano et al, 2011). Interaction of RAB10:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB10 with GDI and CHM proteins.
R-HSA-8876190 (Reactome) RAB8 is involved in trafficking from the trans-Golgi network (TGN) to the plasma membrane, contributes, with RAB10, 13 and 14 to GLUT4 transport, and plays a role in the formation of the primary cilium (Huber et al, 1993; Ishikura et al, 2008; Sun et al, 2010; Nachury et al, 2007; Yoshimura et al, 2007; reviewed in Hoffman and Elmendorf, 2011; Reiter et al, 2012). RAB8 also plays a role in regulating G2/M transition in complex with Optineurin (OPTN) (Kachaner et al, 2012).

RAB3IP is the best characterized GEF for RAB8A, with established roles in ciliogenesis (Hatulla et al, 2002; Knodler et al, 2010; Westlake et al, 2012; Wang et al, 2012; Feng et al, 2012; reviewed in Sung and Leroux, 2013). Other potential RAB8 GEFs include RAB3IPL and DENND1C (Yoshimura et al, 2010; reviewed in Ishida et al, 2016). Interaction of RAB8 with its GEFs displaces the GDI or CHM protein that keeps the inactive RAB:GDP soluble in the cytosol and promotes membrane association of RAB8 (reviewed in Wandinger-Ness and Zerial, 2014; Ishida et al, 2016)
R-HSA-8876191 (Reactome) RAB9 plays a role in the retrograde traffic of cargo such as the mannose-6-phosphate receptors (M6PR) from the late endosome to the trans-Golgi network (TGN). Vesicles are recruited to the TGN through interaction of RAB9 with the atypical RHO GTPase RHOBTB3, and tethered by virtue of interaction with TGN-localized Golgins and the GARP complex (Perez-Victoria et al, 2008; Perez-Victoria et al, 2009; Diaz et al, 1999; Espinosa et al, 2009; reviewed in Pfeffer, 2011; Chia and Gleeson, 2014). Interaction of RAB9:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB9 with GDI and CHM proteins. DENND2 family members have been shown to be RAB9 specific GEFs, and HeLa cells depleted of RAB9 or DENND2A show reduced staining of M6PR and a loss of M6PR-positive structures in the cell periphery (Yoshimura et al, 2010).
R-HSA-8876193 (Reactome) The RIC1:RGP1 complex is a GEF for RAB6, the primary RAB in intra-Golgi trafficking. RAB6 also has roles in COPI-independent retrograde traffic from the Golgi to the ER. Inactive RAB6:GDP is recruited to the trans-Golgi network (TGN) through interaction with RIC1:RGP1, and is subsequently activated by the RIC1:RGP1 GEF activity (Pusapati et al, 2012; Siniossoglou et al 2001; Siniossoglou et al, 2000; reviewed in Ishida et al, 2016). Interaction of RIC1:RGP1 with RAB6:GDP promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB6 with GDI and CHM proteins. Activated RAB6 nucleates a tethering complex at the TGN that is required for fusion of endosome-derived vesicles arriving at the late Golgi. Typical cargo of the RAB6-dependent retrograde vesicles include resident TGN proteins such as TGOLN2 as well as Shiga, cholera and ricin toxins which use the retrograde trafficking machinery to 'hitchhike' back through the secretory system for release into the cytoplasm (Siniossoglou et al, 2001; Liewen et al, 2005; Perez-Victoria et al, 2008; Perez-Victoria et al, 2009; reviewed in Bonaficino and Hierro, 2011; Johannes and Popoff, 2008; Pfeffer, 2011).


R-HSA-8876446 (Reactome) ULK1 is a serine-threonine kinase with key roles in macroautophagy in response to starvation. Under high nutrient conditions, ULK1 is phosphorylated by mTORC1, inhibiting the autophagy pathway, while under nutrient-limited conditions, mTORC1 phosphorylation is replaced by AMPK-mediated phosphorylation, resulting in the activation of both ULK1 and the autophagy pathway (reviewed in Wong et al, 2013). How nutrient levels are sensed by mTORC1 and ULK1 is not fully established, but a number of recent papers have highlighted a role for RAB proteins and their regulators in autophagy (Matsui and Fukuda, 2013; Matsui et al, 2014; Xu et al, 2015; Fan et al, 2016; reviewed in Lamb et al, 2013; Xu and McPherson, 2015). Under starvation conditions, ULK1 phosphorylates DENND3, a RAB12 GEF, at serine residues 472 and 490, activating it and promoting the formation of GTP-bound RAB12 (Yoshimura et al, 2010; Xu et al, 2015). Active RAB12 promotes the constitutive recycling or degradation of a number of plasma membrane proteins including the amino acid transporter SLC36A4 (also known as PAT4). Degradation of SLC36A4 decreases the intracellular amino acid concentration, inactivating mTORC1 and promoting the macroautophagy pathway (Matsui et al, 2011; Matsui and Fukuda, 2013; Xu et al, 2015; Fan et al, 2016).
R-HSA-8876454 (Reactome) DENND3 is a RAB12-specific GEF with roles in macroautophagy and the trafficking of proteins from the recycling endosome to the lysosome (Yoshimura et al, 2010; Matsui et al, 2014; Xu et al, 2015; reviewed in Xu and McPherson, 2015). DENND3 activity promotes the formation of active RAB12:GTP, required for the constitutive degradation of plasma membrane proteins such as the transferrin receptor and the amino acid transporter SLC36A4, also known as PAT4 (Matsui et al, 2011; Matsui and Fukuda, 2013; Matsui et al, 2014; Sirohi et al, 2013). Under starvation conditions, DENND3 is phosphorylated by the macroautophagy-promoting kinase ULK1. DENND3- and RAB12-dependent degradation of SLC36A4 contributes to the activation of the macroautophagy pathway by decreasing intracellular amino-acid levels and inhibiting mTORC1 (Matsui and Fukuda, 2013; Matsui et al, 2014; Xu et al, 2015; Fan et al, 2016; reviewed in Xu and McPherson, 2015).
R-HSA-8876615 (Reactome) RAB13 is involved in the trafficking of proteins in the biosynthetic and endosomal recycling pathways and contributes to processes such as tight junction formation and cell adhesion, GLUT 4 transport, angiogenesis, reorganization of the actin cytoskeleton, cell migration and cellular proliferation (Marzesco et al, 2002; Kohler et al, 2004; Morimoto et al, 2005; Terai et al, 2006; Yamamura et al, 2008; Nokes et al, 2008; Sun et al, 2010; Sakane et al, 2010; Sun et al, 2012; Nishikimi et al, 2014; Sun et al, 2016). These processes are often misregulated in cancer cells, and consistent with this, RAB13 has been implicated as a driver of cancer progression and is upregulated in multiple cancer types (Mahadevan et al, 2005; Li et al, 2014; Ioannou et al, 2015; reviewed in Iaonnou and McPherson, 2016). RAB13 is activated at the plasma membrane by its GEFs, DENND1C and DENND2B (also known as ST5), and may also be activated at other sites at lower levels (Yoshimura et al, 2010; Marat et al, 2012; Nishikimi et al, 2014; Ioannou et al, 2015; reviewed in Ishida et al, 2016). In this reaction, GDI and CHM proteins are depicted keeping the inactive, GDP-bound RAB13 soluble, in accordance with the classic view of the RAB cycle. A recent paper, however, provides evidence that in the case of RAB13, inactive RAB13:GDP traffics on vesicles, tethered by interaction with vesicle-bound proteins, and resists GDI-dependent extraction from membranes (Ioannou et al, 2016).
R-HSA-8876616 (Reactome) RAB14 is involved in the trafficking of GLUT4 to the plasma membrane and also contributes to cell migration by regulating the trafficking of ADAM10, a metalloendopetidase that cleaves a number of cell surface proteins including the adherens junction components N-cadherin (Reed et al, 2013; Brewer et al, 2016; Linford et al, 2012; Lu et al, 2012; Maretzky et al, 2005; Reiss et al, 2005; Gutwein et al, 2010; Rabquer et al, 2010). DENND6A and B, also known as FAM116A and B, show RAB14 GEF activity in vitro and are required for RAB14 localization and activity in vivo (Linford et al, 2012; reviewed in Ishida et al, 2016). Interaction of RAB14:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB14 with GDI and CHM proteins.


R-HSA-8876837 (Reactome) RAB21 is involved in the endocytosis of transferrin and EGF receptors as well as of integrins, and RAB21-mediated integrin trafficking is required for cytokinesis (Simpson et al, 2004; Pellinen et al, 2006; Pellinen et al, 2008; reviewed in Miserey-Lenkei and Colombo, 2016). In addition, RAB21 contributes to neurite and dendrite outgrowth, macrophage outgrowth and fusion of autophagosomes with lysosomes (Obayashi et al, 2012; Burgo et al, 2009; Burgo et al, 2012; Jean et al, 2012; Jean et al, 2015). RAB21 nucleotide exchange is stimulated by ANKRD27, also known as VARP (VPS9 ankyrin repeat protein), which in addition to promoting RAB21 guanyl-nucleotide exchange, also interacts with numerous RAB effectors and contributes to multiple steps of endosomal trafficking (Zhang et al, 2006; Obayashi et al, 2012; reviwed in Fukuda, 2016; Ishida et al, 2016). Other GEFs for RAB21 include the myotubularin proteins SBF1 and SBF2 (also known as MTMR5 and MTMR13) which contribute to macrophage outgrowth and fusion of autophagosomes with lysosomes (Jean et al, 2012; Jean et al, 2015). Interaction of RAB21:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB21 with GDI and CHM proteins.
R-HSA-8877308 (Reactome) Vertebrate RAB27 exists in two isoforms, RAB27A and RAB27B, with overlapping but distinct functions in trafficking to melanosomes, secretory granules and platelets (Kondo et al, 2006; Figueiredo et al, 2008; Tarafder et al, 2011; reviewed in Fukuda et al, 2013). Studies in nematodes and vertebrates have identified MADD as a RAB27 GEF required for its activity (Mahoney et al, 2006; Tarafder et al, 2011; Yoshimura et al, 2010). Interaction of RAB27:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB27 with GDI and CHM proteins.
R-HSA-8877311 (Reactome) RAB31, also referred to as RAB22B, is a member of the RAB5 family of proteins (Chen et al, 1996; Bao et al, 2002). It is involved in trafficking pathways at the trans-Golgi network (TGN) and early endosome, where it is required for insulin-stimulated GLUT4 transport, internalization of the EGFR receptor and for mannose-6-phosphate receptor transport from the TGN (Rodriguez-Gabin et al, 2001; Lodhi et al, 2007; Chua et al, 2014; Ng et al, 2007; Ng et al, 2009; Rodriguez-Gabin et al, 2009). RAB31 overexpression is also implicated in cellular proliferation and apoptosis during cancer progression (Pan et al, 2015; reviewed in Chua and Tang, 2015). RAB31 is activated by VPS domain-containing GEFs GAPVD1 (also known as GAPEX5 or RAP6) and RIN3 (Hunker et al, 2006; Lodhi et al, 2007; Kajiho et al, 2003; Kajiho et al, 2011). Interaction of RAB31:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB31 with GDI and CHM proteins.
R-HSA-8877451 (Reactome) RAB7 acts downstream of RAB5 in a RAB cascade that regulates endolysosomal trafficking (Chavrier et al, 1990; Feng et al, 1997; Vitelli et al, 1997; reviewed in Epp et al, 2011; Solinger and Spang, 2013). The RAB7 GEF complex, MON:CCZ1, is recruited to the endosome through interaction with RAB5 and the RAB5 effector complex CORVET (Nordmann et al, 2010; Gerondopolous et al, 2012; Poteryaev et al, 2010; Wang et al, 2002; Kinchen and Ravichandran, 2010; reviewed in Wang et al, 2011; Balderhaar and Ungermann, 2013). Recruitment of MON1:CCZ1 leads to the displacement RAB5 and the RAB5 GEF RABEX5, and subsequent recruitment and activation of RAB7 (Poteryaev et al, 2010; reviewed in Balderhaar and Ungermann, 2013; Wandinger-Ness and Zerial, 2014; Ishida et al, 2016). RAB7 is also involved in more specialized trafficking pathways involved in phagocytosis, autophagy and retromer-mediated endocytosis, among others (Gutierrez et al, 2004; Harrison et al, 2003; Cantalupo et al, 2003; reviewed in Hyttinen et al, 2013)
R-HSA-8877475 (Reactome) RAB1 is involved in COPII-mediated anterograde traffic from the endoplasmic reticulum to the ERGIC (ER-Golgi intermediate compartment) and in early steps of the macroautophagy pathway (reviewed in Szul and Sztul, 2011; Sandoval and Simmen, 2012; Lord et al, 2013; Yang et al, 2016; Lamb et al, 2016; Kim et al, 2016; Ao et al, 2014). RAB1 nucleotide exchange is stimulated in these pathways by the GEF activity of the multisubunit TRAPPC complexes II and III, respectively (reviewed in Brunet and Sacher, 2014; Kim et al, 2016). Note that the separate existence of a TRAPPCI complex is not clearly established in human cells (Barrowman et al, 2010; Bassik et al, 2013; reviewed in Brunet and Sacher, 2014; Kim et al, 2016). TRAPPCII is recruited to ER-derived vesicles by virtue of an interaction between the TRAPPCII component TRAPPC3 and the COPII coat protein SEC23 (Wang et al, 2000; Cai et al, 2007; Cai et al, 2008; Yamasaki et al, 2009; Lord et al, 2011; reviewed in Brunet and Sacher, 2014; Ishida et al, 2016). Interaction of TRAAPPCII with RAB1:GDP promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB1 with GDI and CHM proteins. Protein protein interactions involving activated RAB1:GTP help dock the ER-derived vesicle on the cis-Golgi membrane (reviewed in Lord et al, 2013). In the macroautophagy pathway, RAB1 and the TRAPPCIII complex play a role in the formation of the pre-autophagosomal structure (PAS) and contribute to the localization of ATG9, a key nucleator of autophagosome formation (Lynch-Day et al, 2010; Winslow et al, 2010; Zoppino et al, 2010; Mochizuki et al, 2013; Lamb et al, 2016; reviewed in Kim et al, 2016).
R-HSA-8877612 (Reactome) RAB35 localizes to the plasma membrane, to clathrin-coated vesicles and to the endosome where it plays roles in recycling of endocytic cargo to the plasma membrane, in synaptic vesicle recycling and fusion of exosomes. RAB35 is also required for cytokinesis and contributes to the regulation of the actin cytoskeleton, and for GLUT4 translocation to the plasma membrane in response to insulin (Fuchs et al, 2007; Allaire et al, 2010; Kouranti et al, 2006; Dambournet et al, 2011; Rahajeng et al, 2012; Hsu et al. 2010; Uytterhoeven et al. 2011; Zhang et al. 2009; Davey et al, 2012; Humphrey et al, 2013; reviewed in Klinkert and Echard, 2016). RAB35 is activated by DENND1A, B and C (Sato et al, 2008; Allaire et al, 2010; Yoshimura et al, 2010; Marat and McPherson, 2010; Marat et al, 2012; reviewed in Marat et al, 2011; Ishida et al, 2016). Interaction of RAB35:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB35 with GDI and CHM proteins (Wu et al, 2011).
R-HSA-8877760 (Reactome) RAB32 and RAB38 play non-redundant but overlapping roles in melanosome and lysosome-related organelle (LRO) biogenesis (Loftus et al, 2002; Wasmeier et al, 2006; Lopes et al, 2007; Wang et al, 2008; Bultema et al, 2012; reviewed in Bultema and di Pietro, 2012). Through interaction with effector protein ANKRD27 (also known as VARP, a RAB21-specific GEF), RAB32 and RAB38 control trafficking of melanogenic enzymes; ANKRD27 GEF activity does not appear to be essential for this, however (Tamura et al, 2009; Tamura et al, 2011; Ohbayahsi et al, 2012). BLOC-3, a dimeric complex of HPS1 and HPS4, has RAB32- and RAB38 GEF activity and mutation in the genes encoding HPS1 and HPS4 results in defects in pigmentation and mislocalization of RAB32 and 38, and are associated with the rare autosomal recessive disorder Hermansky-Pudlak Syndrome (Gerondopoulos et al, 2012; reviewed in Ishida et al, 2016). Interaction of RAB32:GDP or RAB38:GDP with BLOC-3 promotes release of GDP, allowing GTP to bind, and precludes the interaction of the RAB proteins with GDI and CHM proteins.
R-HSA-8877813 (Reactome) RAB39 proteins are involved in endolysosomal trafficking and are localized to the Golgi membrane where they interact with the multisubunit tethering complex COG (Chen et al, 2003; Giannandrea et al, 2010; Miller et al, 2013; reviewed in Willet et al, 2013). Although RAB proteins are known to play key roles in trafficking and Golgi structure and function, the significance of some of these interactions is not yet clear (reviewed in Liu and Storrie, 2015). Loss-of-function mutations of RAB39B cause X-linked metal retardation, likely as a result of altered trafficking during growth cone and synapse formation (Giannandrea et al, 2010). Activation of RAB39 at the Golgi is dependent on the GEF activity of DENND5A and DENND5B (Yoshimura et al, 2010). Interaction of RAB39:GDP with its GEFs promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB39 with GDI and CHM proteins.
R-HSA-8877998 (Reactome) RAB18 is a highly conserved RAB GTPase with roles in Golgi to ER trafficking, lipid droplet formation and the regulation of secretory granules and peroxisomes (Dejgaard et al, 2008; Gerondopoulos et al, 2014; Martin et al, 2005; Ozeki et al, 2005; Vazquez-Martinez et al, 2007; Gronemeyer et al, 2013). RAB18 is recruited to the ER membrane by the RAB18 GEF complex RAB3GAP1:RAB3GAP2, a complex that was initially identified and characterized for its GAP activity towards RAB3 (Gerondopoulos et al, 2013; Fukui et al, 1997; Nagano et al, 1998; reviewed in Ishida et al, 2016). Interaction of RAB18:GDP with its GEF promotes release of GDP, allowing GTP to bind, and precludes the interaction of RAB18 with GDI and CHM proteins. Mutations in RAB18, RAB3GAP1 or RAB3GAP2 are associated with Warburg Micro syndromes, characterized by ocular and neurological abnormalities (Handley and Aligianis, 2013; reviewed in Handley and Aligianis, 2012).
R-HSA-8933446 (Reactome) In response to insulin signaling, active AKT phosphorylates the C-terminal region of RAB35 GEFs DENND1A and DENND1B at at least 2 sites in the C-terminal region. This relieves an autoinhibitory conformation of the GEFs, allowing full GEF activity and promoting RAB35 binding. The open conformation of DENN1D proteins is stabilized subsequent to AKT-mediated phosphorylation by binding of a dimer of the 14-3-3 protein YWHAE. Abrogation of AKT phosphorylation disrupts both 14-3-3 and RAB35 binding to DENND1 proteins (Kulasekaran et al, 2015). Active RAB35 is needed for the insulin-dependent translocation of GLUT4 to the plasma membrane (Davey et al, 2012; Humphrey et al, 2013).
R-HSA-8933452 (Reactome) RAB35 GEFs DENND1A and DENND1B are phosphorylated by AKT in response to insulin signaling at at least 2 sites in the C-terminal region. This phosphorylation relieves an autoinhibitory conformation of the GEF that sterically blocks the N-terminal DENN domain, obstructing RAB35 binding and full GEF activity. Subsequent to AKT-dependent phosphorylation, DENN1D proteins are bound by a 14-3-3 dimer, which is thought to stabilize the open conformation of the GEF, promoting full GEF activity and RAB35 binding (Kulasekaran et al, 2015). Active RAB35 contributes to GLUT4 translocation to the plamsa membrane in response to insulin signaling, among other cellular roles (Kulasekaran et al, 2015; Davey et al, 2012; Humphrey et al, 2013).
RAB13 GEFsmim-catalysisR-HSA-8876615 (Reactome)
RAB21 GEFsmim-catalysisR-HSA-8876837 (Reactome)
RAB27:GTPArrowR-HSA-8877308 (Reactome)
RAB3 GEFsmim-catalysisR-HSA-8875318 (Reactome)
RAB31 GEFsmim-catalysisR-HSA-8877311 (Reactome)
RAB32,RAB38:GDP:GDIs,CHMsR-HSA-8877760 (Reactome)
RAB32,RAB38:GTPArrowR-HSA-8877760 (Reactome)
RAB35 GEFsmim-catalysisR-HSA-8877612 (Reactome)
RAB3GAP1:RAB3GAP2mim-catalysisR-HSA-8877998 (Reactome)
RAB5 GEFsmim-catalysisR-HSA-8875320 (Reactome)
RAB8 GEFsmim-catalysisR-HSA-8876190 (Reactome)
RAB9 GEFsmim-catalysisR-HSA-8876191 (Reactome)
RIC1:RGP1mim-catalysisR-HSA-8876193 (Reactome)
TRAPPCsmim-catalysisR-HSA-8877475 (Reactome)
YWHAE dimerR-HSA-8933452 (Reactome)
p-2S DENND1A, DENND1BArrowR-HSA-8933446 (Reactome)
p-2S DENND1A, DENND1BR-HSA-8933452 (Reactome)
p-2S-DENND1A,B:YWHAE dimerArrowR-HSA-8933452 (Reactome)
p-S472,S490-DENND3ArrowR-HSA-8876446 (Reactome)
p-T180,S317,S467,S556,S638,T575-ULK1mim-catalysisR-HSA-8876446 (Reactome)
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