The secretory membrane system allows a cell to regulate delivery of newly synthesized proteins, carbohydrates, and lipids to the cell surface, a necessity for growth and homeostasis. The system is made up of distinct organelles, including the endoplasmic reticulum (ER), Golgi complex, plasma membrane, and tubulovesicular transport intermediates. These organelles mediate intracellular membrane transport between themselves and the cell surface. Membrane traffic within this system flows along highly organized directional routes. Secretory cargo is synthesized and assembled in the ER and then transported to the Golgi complex for further processing and maturation. Upon arrival at the trans Golgi network (TGN), the cargo is sorted and packaged into post-Golgi carriers that move through the cytoplasm to fuse with the cell surface. This directional membrane flow is balanced by retrieval pathways that bring membrane and selected proteins back to the compartment of origin.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=199991
Comments
HomologyConvert
This pathway was inferred from Homo sapiens pathway WP1846(76873) with a 75.0% conversion rate.
Hammond AT, Glick BS.; ''Dynamics of transitional endoplasmic reticulum sites in vertebrate cells.''; PubMedEurope PMCScholia
Zhu Y, Traub LM, Kornfeld S.; ''ADP-ribosylation factor 1 transiently activates high-affinity adaptor protein complex AP-1 binding sites on Golgi membranes.''; PubMedEurope PMCScholia
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Sachse M, Strous GJ, Klumperman J.; ''ATPase-deficient hVPS4 impairs formation of internal endosomal vesicles and stabilizes bilayered clathrin coats on endosomal vacuoles.''; PubMedEurope PMCScholia
Lippincott-Schwartz J, Roberts TH, Hirschberg K.; ''Secretory protein trafficking and organelle dynamics in living cells.''; PubMedEurope PMCScholia
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Musacchio A, Smith CJ, Roseman AM, Harrison SC, Kirchhausen T, Pearse BM.; ''Functional organization of clathrin in coats: combining electron cryomicroscopy and X-ray crystallography.''; PubMedEurope PMCScholia
Claude A, Zhao BP, Kuziemsky CE, Dahan S, Berger SJ, Yan JP, Armold AD, Sullivan EM, Melançon P.; ''GBF1: A novel Golgi-associated BFA-resistant guanine nucleotide exchange factor that displays specificity for ADP-ribosylation factor 5.''; PubMedEurope PMCScholia
Cukierman E, Huber I, Rotman M, Cassel D.; ''The ARF1 GTPase-activating protein: zinc finger motif and Golgi complex localization.''; PubMedEurope PMCScholia
Bryant NJ, Govers R, James DE.; ''Regulated transport of the glucose transporter GLUT4.''; PubMedEurope PMCScholia
Zaid H, Antonescu CN, Randhawa VK, Klip A.; ''Insulin action on glucose transporters through molecular switches, tracks and tethers.''; PubMedEurope PMCScholia
Scheuring S, Röhricht RA, Schöning-Burkhardt B, Beyer A, Müller S, Abts HF, Köhrer K.; ''Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking.''; PubMedEurope PMCScholia
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Bogan JS, Kandror KV.; ''Biogenesis and regulation of insulin-responsive vesicles containing GLUT4.''; PubMedEurope PMCScholia
Maier O, Knoblich M, Westermann P.; ''Dynamin II binds to the trans-Golgi network.''; PubMedEurope PMCScholia
Antonin W, Holroyd C, Fasshauer D, Pabst S, Von Mollard GF, Jahn R.; ''A SNARE complex mediating fusion of late endosomes defines conserved properties of SNARE structure and function.''; PubMedEurope PMCScholia
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The ferritin complex is an oligomer of 24 subunits with light and heavy chains. The major chain can be light or heavy, depending on the tissue type. The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron metabolism provides a useful example of gene expression translational control. Increased iron levels stimulate the synthesis of the iron-binding protein, ferritin, without any corresponding increase in the amount of ferritin mRNA. The 5?-UTR of both ferritin heavy chain mRNA and light chain mRNA contain a single iron-response element (IRE), a specific cis-acting regulatory sequence which forms a hairpin structure.
Gap junctions are clusters of intercellular channels connecting adjacent cells and permitting the direct exchange of ions and small molecules between cells. These channels are composed of two hemichannels, or connexons, one located on each of the two neighboring cells. Each connexon is composed of 6 trans-membrane protein subunits of the connexin (Cx) family. A gap of approximately 3 nm remains between the adjacent cell membranes, but two connexons interact and dock head-to-head in the extra-cellular space forming a tightly sealed, double-membrane intercellular channel (see Segretain and Falk, 2004). The activity of these intercellular channels is regulated, particularly by intramolecular modifications such as phosphorylation which appears to regulate connexin turnover, gap junction assembly and the opening and closure (gating) of gap junction channels.
In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011). In myocytes muscle contraction alone can also cause translocation of GLUT4. Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins. Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane.
Ultimately the hydrolysis of Arf1-bound GTP, induced by the recruited ArfGAP, allows the inactive Arf1-GDP to diffuse away from the membrane, initiating disassembly of the lattice from the vesicle (Lippincott-Schwartz and Liu 2006).
The formation of the COPI coat requires membrane recruitment and activation of Arf1. Arf1 activation is normally mediated by guanine nucleotide exchange factors (GEFs) that convert Arf1 to its active GTP-bound state on the membrane. In this reaction that GEF is represented by GBF1.
Together, the complex of coatomer, Arf1, and ArfGAP assembles into a lattice that concentrates cargo proteins and deforms the membrane. Eventually this membrane pocket forms into a bud that pinches off the membrane, and is released into the cytoplasm (Lippincott-Schwartz and Liu 2006).
All of the key components and regulators of the COPI coat (GBF1, Arf1, ArfGAP1 and coatomer) cycle on and off the Golgi membrane. This cycle is required for vesicle formation, but is uncoupled from the actual vesicle release. Continuous membrane binding and release of these molecules enables the COPI lattice to be dynamically modulated. Once the vesicle is released from the Golgi apparatus, this lattice is completely disassociated from the vesicle.
In models of COPI coat assembly and disassembly, after GBF1 activates Arf1 on membranes, the active form of Arf1 recruits coatomer complexes from the cytoplasm.
Sar1p-GTP recruits the cytoplasmic Sec23p-Sec24p complex. Though not represented in the subsequent steps, Sec23p-Sec24p would bind to members of the p24 protein family of possible cargo receptors, and together with Sar1p bind the appropiate v-SNARE, and Rab-GTP.
Sar1p-GTP hydrolysis is increased 15-30-fold by Sec23p. Sar1p-GDP is released as a result of this hydrolysis and used in further vesicle sculpting cycles. Sar1p-GTP hydrolysis occurs at two critical points during the cycle, first (as represented here) as a proofreading step, insuring that the cargo is loaded. Later in the cycle Sar1p-GTP hydrolysis triggers the uncoating of the budded vesicle.
ARF1 helps to recruit AP-1 to Golgi membrane. AP-1 is not alone in this process of establishing a docking complex at the trans-Golgi Network. This section of the Golgi membrane will be where the new vesicle will be built and loaded.
The heat shock protein Hsc70 and auxilin, a J-domain containing protein, are responsible for clathrin disassembly through an ATP-dependent reaction. This uncoating step may be a point in the pathway subject to regulation. This final step releases the vesicle from the clathrin cage. The vesicle still contatins a specific Vamp molecule, part of the targeting and fusion mechanism that delivers the vesicle to its ultimate destination. This vesicle also contains its cargo, membrane proteins embeded in the Golgi-associated vesicle membrane.
Once the basic components of the docking complex are assembled with one end of AP-1 bound to cargo molecules, the other end binds to clathrin. Clathrin triskelions polymerize into hexagons and pentagons, forming a cage, which leads to membrane deformation. This polymerization step drives the sculpting of the lysosome vesicle. Here only 5 clathrin triskelions are represented, though in reality many more would be involved in sculpting an entire vesicle.
Dynamin is recruited to the growing lysosome destined vesicle and, under conditions that interfere with its GTPase activity, dynamin forms a collar or ring around the neck of the budding vesicle. It is unclear whether dynamin acts as a mechanochemical transducer to generate fission or as a recruiter to attach other proteins that are directly responsible for the fission step. Lipid-modifying enzymes such as endophilin are also involved in vesicle formation. Endophilin is an acyltransferase that interacts with dynamin and that generates lysophosphatidic acid. The current view is that this reaction produces a negative curvature at the neck of the vesicle.
The heat shock protein Hsc70 and auxilin, a J-domain containing protein, are responsible for clathrin disassembly through an ATP-dependent reaction. This uncoating step may be a point in the pathway subject to regulation. This final step releases the vesicle from the clathrin cage. The vesicle still contatins a specific Vamp molecule, part of the targeting and fusion mechanism that delivers the vesicle to its ultimate destination. This vesicle also contains its cargo, membrane proteins embeded in the lysosome membrane.
Dynamin is recruited to the growing vesicle and, under conditions that interfere with its GTPase activity, dynamin forms a collar or ring around the neck of the budding vesicle. It is unclear whether dynamin acts as a mechanochemical transducer to generate fission or as a recruiter to attach other proteins that are directly responsible for the fission step. Lipid-modifying enzymes such as endophilin are also involved in vesicle formation. Endophilin is an acyltransferase that interacts with dynamin and that generates lysophosphatidic acid. The current view is that this reaction produces a negative curvature at the neck of the vesicle.
Once the basic components of the docking complex are assembled with one end of AP-1 bound to cargo molecules, the other end binds to clathrin. Clathrin triskelions polymerize into hexagons and pentagons, forming a cage, which leads to membrane deformation. This polymerization step drives the sculpting of the vesicle. The number of clathrin triskelions required to sculpt a vesicle appears to be variable, but has been estimated to require 36 - 60 triskelions assocaited with 30 - 66 AP-1 complexes. Here a ~380 angstroms vesicle is represented with 48 clathrin triskelions and 52 AP-1 complexes.
Once AP-1 is recruited to the trans-Golgi Network membrane the complex of functional vesicle building proteins is joined by the cargo that will be within that vesicle. As with other types of vesicles the cargo itself is part of the vesicle development. Here the cargo is destined for the lysosome membrane. It is at this stage that a specific Synaptobrevin (Vamp) molecule also joins the complex. It should be noted that only certain Vamp molecules will be found with specific cargo molecules on the newly forming vesicles. However here we represent this reaction in bulk, without specific Vamp and cargo molecule pairings.
The ubiquitously expressed protein complexes, named biogenesis of lysosome-related organelles complex or BLOC are required for normal biogenesis of specialized organelles of the endosomal-lysosomal system, such as melanosomes and platelet dense granules.
Once AP-1 is recruited to the trans-Golgi Network membrane the complex of functional vesicle building proteins is joined by the cargo that will be within that vesicle. As with other types of vesicles the cargo itself is part of the vesicle development. Here the cargo is destined for the Golgi-associated vesicle membrane. It is at this stage that a specific Synaptobrevin (Vamp) molecule also joins the complex. It should be noted that only certain Vamp molecules will be found with specific cargo molecules on the newly forming vesicles. However here we represent this reaction in bulk, without specific Vamp and cargo molecule pairings.
Disassembly Phase
The AAA-ATPase, Vps4 disassembles ESCRT-III and catalyzes the final step of the MVB pathway. The microtubule interacting and trafficking (MIT) domain of Vps4 interacts directly with the C-terminal region of Vps2 (MIM1) and Vps20 (MIM2). The association of Vta1, which contains two MIT domains, greatly enhances the activity of Vps4. Please note that the recomended names of the Vacuolar protein sorting-associated proteins (Vps) are Charged multivesicular body proteins or CHMPs.
Initiation/Cargo Recognition is mediated by ESCRT-0, a heterodimer consisting of Vps27 and Hse1. ESCRT-0 binds Phosphatidyl inositol 3- phosphate (PI3P) on endosomes via a FVYE domain and ubiquitinated cargo via two UIM domains.
ESCRT-III assembles into a highly ordered filament-like hetero-oligomer. Vps20 nucleates the homo-oligomerization of Snf7 that is capped by Vps24. Vps24 recruits Vps2 and initiates Vps4-dependent ESCRT-III disassembly. ESCRT-III is required for the last steps of MVB sorting, cargo sequestration, and MVB vesicle formation.
ESCRT-0 recruits ESCRT-I and thereby initiates the MVB pathway. Cargo Sorting ESCRT-I is a heterotetramer consisting of Vps23, Vps28, Vps37, and Mvb12. The UEV domain of Vps23 binds ubiquitinated membrane proteins. Vps28 interacts with the GLUE domain of Vps36 in ESCRT-II. Cargo Sorting ESCRT-II is a heterotetramer formed of Vps36, Vps22, and two Vps25 molecules. The GLUE domain of Vps36 binds PI3P, Vps28, and ubiquitinated membrane proteins. Vps25 interacts with Vps20 of ESCRT-III.
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DataNodes
Triskelion:Vamp
ComplexTriskelion:Dynamin:Endophilin
Complextrafficking and
regulationVesicle Destined
Cargovesicle interacting
proteinsCargo:AP-1:Beta-arrestin:Clathrin Triskelion:Vamp
ComplexCargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp
ComplexCargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin
Complex[endocytic vesicle
membrane]GLUT4 to the Plasma
MembraneThough the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.
Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane.
[endocytic vesicle
membrane][endocytic vesicle
membrane][endocytic vesicle
membrane][endocytic vesicle
membrane][endocytic vesicle
membrane][endocytic vesicle
membrane][endocytic vesicle
membrane][endocytic vesicle
membrane]Endosmal Membrane
Bound CargoSecretory granule docking and fusion
complexPlasma membrane vesicle docking and
fusion complexSecretory granule docking and fusion
complexAnnotated Interactions
Triskelion:Vamp
ComplexTriskelion:Vamp
ComplexTriskelion:Dynamin:Endophilin
ComplexTriskelion:Dynamin:Endophilin
ComplexTriskelion:Dynamin:Endophilin
ComplexVesicle Destined
Cargovesicle interacting
proteinsCargo:AP-1:Beta-arrestin:Clathrin Triskelion:Vamp
ComplexCargo:AP-1:Beta-arrestin:Clathrin Triskelion:Vamp
ComplexCargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp
ComplexCargo:AP-1:Arf1-GTP:beta-Arrestin-1:Vamp
ComplexCargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin
ComplexCargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin
ComplexCargo:AP-1:Beta-arrestin:Vamp:Clathrin Triskelion:Dynamin:Endophilin
ComplexThe AAA-ATPase, Vps4 disassembles ESCRT-III and catalyzes the final step of the MVB pathway. The microtubule interacting and trafficking (MIT) domain of Vps4 interacts directly with the C-terminal region of Vps2 (MIM1) and Vps20 (MIM2). The association of Vta1, which contains two MIT domains, greatly enhances the activity of Vps4. Please note that the recomended names of the Vacuolar protein sorting-associated proteins (Vps) are Charged multivesicular body proteins or CHMPs.
Endosmal Membrane
Bound CargoSecretory granule docking and fusion
complexPlasma membrane vesicle docking and
fusion complexSecretory granule docking and fusion
complex