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    Report for Pathway Review

    Introduction

    This report is intended for reviewers of the pathway "Insulin processing". It has beenautomatically generated.

    Please Note:

    Non-ASCII characters, primarily in author names, are not displayed correctly in this document.We apologize for this inconvenience.

    *

    Each reaction (pathway event) is represented here by a simple diagram. Input molecules areshown as labelled boxes (left side) connected by plain lines to a central square. Arrowed linesconnect the central square to the output molecules (right side). If relevant, catalyst moleculesare represented above the central square, connected to it by a red arrowed line. Inputmolecules that are also the catalyst (e.g. signaling or enzyme/substrate complexes) are shownon the left and joined to the central node by a red arrowed line. The names of reactions thatprecede/follow in the pathway are shown as text on the far left/far right respectively.

    *

    Summary text may appear to be overlapping or redundant. Please remember that this

    document is extracted from multiple pages on the Reactome website, this redundancy is usefulto provide context for users who might first arrive at a mid-point in the pathway. Suggestionsfor improvement are welcome.

    *

    Reactome represents human biology. Literature references that demonstrate the occurrence ofthe reaction in humans are given preference, they are not intended to provide a historicalrecord. Unfortunately we do not have the resources to identify all relevant references, but weare happy to cite any that you feel should be included.

    *

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    Review of text document

    In your review, we would appreciate it if you could verify that the events that we describe(pathways and reactions) are annotated clearly and that the molecular details of the reactions

    are accurate.

    Review of Website Pathway Browser

    A more detailed representation of the pathway as a diagram can be found on our website. Wewould appreciate your feedback on the content and navigability of the website. A short tutorial ofthe Pathway Browser can be found at the top of the webpage. The zoomable pathway diagramis interactive. Text descriptions are revealed in the panel below the diagram under the overviewtab. To view a text description, select a participating molecules or reaction node in the diagram.Clicking on an event in the hierarchy in the left panel will highlight the event(s) in the diagram

    and a text description will be displayed in the panel below.

    Reaction Diagram Key

    A more detailed description of the website and its features can be found in our Users Guide.

    *Note that the "Expression" and "Structure" data are not available before public release as it isprovided by external resources.

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    1 Insulin processing (Pathway)

    Authors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    The generation of insulin-containing secretory granules from proinsulin in the lumen of theendoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfidebonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yieldinsulin, translocation of the granules across the cytosol to the plasma membrane.

    Transcription of the human insulin gene INS is activated by 4 important transcription factors:

    Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at thepromoters of the insulin gene and act synergistically to promote transcription. Expression of thetranscription factors is upregulated in response to glucose.

    The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER)and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which iscleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA isstabilized by glucose.

    In the process annotated in detail here, within the ER, three intramolecular disulfide bonds formbetween cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result ofthe conformation of proinsulin and the oxidizing environment of the ER, which is maintained by

    Ero1-like alpha

    The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. Highconcentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7and the proinsulin forms complexes with zinc and calcium.

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    Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immaturesecretory vesicles (secretory granules) in the cytosol. Within the immature granules theendoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sitesof the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the

    cystine-bonded A and B chains of mature insulin and the C peptide, which will also be secretedwith the insulin. The insulin-zinc-calcium complexes form insoluble crystals within the granule

    The insulin-containing secretory granules are then translocated across the cytosol to the innersurface of the plasma membrane. Translocation occurs initially by attachment of the granules toKinesin-1, which motors along microtubules, and then by attachment to Myosin Va, whichmotors along the microfilaments of the cortical actin network.

    A pancreatic beta cell contains about 10000 insulin granules of which about 1000 are docked atthe plasma membrane and 50 are readily releasable in immediate response to stimulation byglucose or other secretogogues. Docking is due to interaction between the Exocyst proteinsEXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is

    accomplished by interaction between SNARE-type proteins Syntaxin 1A and Syntaxin 4 on theplasma membrane and Synaptobrevin-2/VAMP2 on the granule membrane. Exocytosis is acalcium-dependent process due to interaction of the calcium-binding membrane proteinSynaptotagmin V/IX with the SNARE-type proteins.

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    References

    Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J,Schermerhorn T, Straub SG, Yajima H, Sharp GW, "Triggering and augmentation mechanisms,

    granule pools, and biphasic insulin secretion", Diabetes, 51, 2002, S83-90.

    Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,1998, 189-94.

    Gerber SH, Südhof TC, "Molecular determinants of regulated exocytosis", Diabetes, 51, 2002,S3-11.

    Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS, "Regulation of the insulingene by glucose and fatty acids", J Nutr, 136, 2006, 873-6.

    Rutter GA, Hill EV, "Insulin vesicle release: walk, kiss, pause ... then run", Physiology(Bethesda), 21, 2006, 189-96.

    1.1 Oxidation of cysteine to cystine in Proinsulin (Reaction)

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    Authors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    Cystine bonds are formed in Proinsulin-1 between cysteine residues 31 and 96, cysteineresidues 43 and 109, and cysteine residues 95 and 100. Ero1-like alpha does not directlycatalyze the oxidation of cysteines to cystine. Instead it maintains a suitably oxidizingenvironment for the reactions to occur . Though Ero1-like alpha can act via specific isomerasessuch as P4HB/PDI, there is currently no evidence that formation of cystine bonds in insulinrequires a specific isomerase. Interestingly, even in beta cells of wild type animals, traceamounts of incorrectly bonded proinsulin can be detected. Thus, the formation of correct cystinebonds may involve a period of bond shuffling.

    References

    Chang SG, Choi KD, Jang SH, Shin HC, "Role of disulfide bonds in the structure and activity ofhuman insulin", Mol Cells, 16, 2003, 323-30.

    Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,1998, 189-94.

    Liu M, Li Y, Cavener D, Arvan P, "Proinsulin disulfide maturation and misfolding in theendoplasmic reticulum", J Biol Chem, 280, 2005, 13209-12.

    Liu M, Ramos-Castañeda J, Arvan P, "Role of the connecting peptide in insulin biosynthesis",J Biol Chem, 278, 2003, 14798-805.

    Min CY, Qiao ZS, Feng YM, "Unfolding of human proinsulin. Intermediates and possible role ofits C-peptide in folding/unfolding", Eur J Biochem, 271, 2004, 1737-47.

    Qiao ZS, Min CY, Hua QX, Weiss MA, Feng YM, "In vitro refolding of human proinsulin. Kineticintermediates, putative disulfide-forming pathway folding initiation site, and potential role of

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    C-peptide in folding process", J Biol Chem, 278, 2003, 17800-9.

    1.2 Cystine-bonded Proinsulin translocates from the endoplasmic

    reticulum to the Golgi (BlackBoxEvent)

    Authors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    Proinsulin in the endoplasmic reticulum moves to the Golgi apparatus via vesicles that bud fromthe endoplasmic reticulum.

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    References

    Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,1998, 189-94.

    Orci L, Ravazzola M, Amherdt M, Madsen O, Vassalli JD, Perrelet A, "Direct identification ofprohormone conversion site in insulin-secreting cells", Cell, 42, 1985, 671-81.

    1.3 ZnT6 transports zinc into the golgi apparatus (Reaction)

    Authors

    Jassal, Bijay, 2009-09-11.

    Editors

    Jassal, Bijay, 2009-08-21.

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    Reviewers

    He, Lei, 2009-11-12.

    Two human genes mediate the transport of zinc into the TGN and they are both localized to theTGN. The human gene SLC30A6 encodes the zinc transporter ZnT6. By Western blot studies,ZnT6 is only found in the brain and lung in human (Huang L et al, 2002).

    References

    Huang L, Kirschke CP, Gitschier J, "Functional characterization of a novel mammalian zinctransporter, ZnT6", J Biol Chem, 277, 2002, 26389-95.

    1.4 ZnT7 transports zinc into the golgi apparatus (Reaction)

    Authors

    Jassal, Bijay, 2009-09-11.

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    Editors

    Jassal, Bijay, 2009-08-21.

    Reviewers

    He, Lei, 2009-11-12.

    The human gene SLC30A7 encodes the zinc transporter ZnT7. It is thought to be present in thesmall intestine and lung in humans (Kirschke CP and Huang L, 2003). Functional propertiesassigned to ZnT7 are based on studies conducted with mouse experiments.

    References

    Kirschke CP, Huang L, "ZnT7, a novel mammalian zinc transporter, accumulates zinc in theGolgi apparatus", J Biol Chem, 278, 2003, 4096-102.

    Source reaction

    This reaction was inferred from the corresponding reaction "Znt7 transports zinc into the golgiapparatus" in species Mus musculus.

    The mouse SLC30A7 gene encodes Znt7 and is detected in many tissues such as liver, kidney,heart and brain by Northern blot analysis. Stable expression of Znt7 in CHO cells results in zincaccumulation in the golgi apparatus (Kirschke CP, Huang L, 2003).

    The following literature references support the source reaction:

    Kirschke CP, Huang L, "ZnT7, a novel mammalian zinc transporter, accumulates zinc in theGolgi apparatus", J Biol Chem, 278, 2003, 4096-102.

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    1.5 Proinsulin binds zinc and calcium formingProinsulin:zinc:calcium (Reaction)

    Authors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    In the presence of high concentrations of zinc and calcium, proinsulin spontaneously formssoluble complexes containing 6 molecules of proinsulin, 2 zinc ions, and 1 calcium ion. ZincTransporters ZnT5, ZnT6, and ZnT7 are found in the membrane of the Golgi in pancreatic cells(and also in many other cell types). They play a role in maintaining the high zinc concentration inthe Golgi lumen and thus catalyze the formation of the proinsulin-zinc-calcium complex. Othertransporters, such as the newly identified ZnT9 and ZnT10, may also be involved but this ispresently unknown.

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    References

    Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,1998, 189-94.

    Dunn MF, "Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- areview", Biometals, 18, 2005, 295-303.

    Kaarsholm NC, Ko HC, Dunn MF, "Comparison of solution structural flexibility and zinc bindingdomains for insulin, proinsulin, and miniproinsulin", Biochemistry, 28, 1989, 4427-35.

    Kadima W, "Role of metal ions in the T- to R-allosteric transition in the insulin hexamer",Biochemistry, 38, 1999, 13443-52.

    Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M, "Overview of mammalian zinc transporters",Cell Mol Life Sci, 61, 2004, 49-68.

    1.6 Proinsulin:Zinc:Calcium complex translocates to immaturesecretory granule (BlackBoxEvent)

    Authors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

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    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    Immature, clathrin-coated vesicles containing proinsulin-zinc-calcium complexes bud from thetrans-golgi network.

    References

    Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,1998, 189-94.

    Orci L, Ravazzola M, Amherdt M, Madsen O, Vassalli JD, Perrelet A, "Direct identification ofprohormone conversion site in insulin-secreting cells", Cell, 42, 1985, 671-81.

    1.7 Processing of Proinsulin to Insulin (BlackBoxEvent)

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    Authors

    May, B, 2008-05-13 13:18:27.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    Proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases Convertase 1/3and Convertase 2. The exopeptidase Carboxypeptidase E then removes 2 amino acids from thecarboxyl termini. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex isnot soluble and forms crystals inside the secretory granules.

    References

    Aldibbiat A, Marriott CE, Scougall KT, Campbell SC, Huang GC, MacFarlane WM, Shaw JA,"Inability to process and store proinsulin in transdifferentiated pancreatic acinar cells lacking theregulated secretory pathway", J Endocrinol, 196, 2008, 33-43.

    Bailyes EM, Shennan KI, Usac EF, Arden SD, Guest PC, Docherty K, Hutton JC, "Differencesbetween the catalytic properties of recombinant human PC2 and endogenous rat PC2",Biochem J, 309, 1995, 587-94.

    Chen H, Jawahar S, Qian Y, Duong Q, Chan G, Parker A, Meyer JM, Moore KJ, Chayen S,Gross DJ, Glaser B, Permutt MA, Fricker LD, "Missense polymorphism in the humancarboxypeptidase E gene alters enzymatic activity", Hum Mutat, 18, 2001, 120-31.

    Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J,Van Lommel L, Grunwald D, Favier A, Seve M, "In vivo expression and functionalcharacterization of the zinc transporter ZnT8 in glucose-induced insulin secretion", J Cell Sci,119, 2006, 4199-206.

    Dodson G, Steiner D, "The role of assembly in insulin's biosynthesis", Curr Opin Struct Biol, 8,1998, 189-94.

    Dunn MF, "Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- a

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    review", Biometals, 18, 2005, 295-303.

    Irminger JC, Meyer K, Halban P, "Proinsulin processing in the rat insulinoma cell line INS afteroverexpression of the endoproteases PC2 or PC3 by recombinant adenovirus", Biochem J, 320,

    1996, 11-5.Itoh Y, Tanaka S, Takekoshi S, Itoh J, Osamura RY, "Prohormone convertases (PC1/3 andPC2) in rat and human pancreas and islet cell tumors: subcellular immunohistochemicalanalysis", Pathol Int, 46, 1996, 726-37.

    Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ,Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A,Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S,"Small-intestinal dysfunction accompanies the complex endocrinopathy of human proproteinconvertase 1 deficiency", J Clin Invest, 112, 2003, 1550-60.

    Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC,O'Rahilly S, "Obesity and impaired prohormone processing associated with mutations in thehuman prohormone convertase 1 gene", Nat Genet, 16, 1997, 303-6.

    Kadima W, "Role of metal ions in the T- to R-allosteric transition in the insulin hexamer",Biochemistry, 38, 1999, 13443-52.

    Kaufmann JE, Irminger JC, Mungall J, Halban PA, "Proinsulin conversion in GH3 cells aftercoexpression of human proinsulin with the endoproteases PC2 and/or PC3", Diabetes, 46, 1997,978-82.

    Malide D, Seidah NG, Chretien M, Bendayan M, "Electron microscopic immunocytochemicalevidence for the involvement of the convertases PC1 and PC2 in the processing of proinsulin inpancreatic beta-cells", J Histochem Cytochem, 43, 1995, 11-9.

    Orci L, Ravazzola M, Amherdt M, Madsen O, Vassalli JD, Perrelet A, "Direct identification ofprohormone conversion site in insulin-secreting cells", Cell, 42, 1985, 671-81.

    Smeekens SP, Montag AG, Thomas G, Albiges-Rizo C, Carroll R, Benig M, Phillips LA, MartinS, Ohagi S, Gardner P, "Proinsulin processing by the subtilisin-related proprotein convertasesfurin, PC2, and PC3", Proc Natl Acad Sci U S A, 89, 1992, 8822-6.

    Smith GD, Pangborn WA, Blessing RH, "The structure of T6 human insulin at 1.0 A resolution",

    Acta Crystallogr D Biol Crystallogr, 59, 2003, 474-82.

    Steiner DF, "The proprotein convertases", Curr Opin Chem Biol, 2, 1998, 31-9.

    Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner DF, "Severe block in processing ofproinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of

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    mice lacking prohormone convertase 1/3", Proc Natl Acad Sci U S A, 99, 2002, 10299-304.

    1.8 ZnT5 transports zinc into secretory granules in pancreatic beta

    cells (Reaction)

    Authors

    Jassal, Bijay, 2009-09-11.

    Editors

    Jassal, Bijay, 2009-08-21.

    Reviewers

    He, Lei, 2009-11-12.

    The human gene SLC30A5 encodes the zinc transporter ZnT5. This protein is widely expressedbut is most abundant in pancreatic beta cells (Kambe T et al, 2002). In these cells, ZnT5mediates the transport of zinc into secretory granules that contain insulin.

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    References

    Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, Sugiura N, Sasaki R, Mori K,Iwanaga T, Nagao M, "Cloning and characterization of a novel mammalian zinc transporter, zinc

    transporter 5, abundantly expressed in pancreatic beta cells", J Biol Chem, 277, 2002,19049-55.

    1.9 SLC30A8 transports Zn2+ from cytosol to secretory granule(Reaction)

    Authors

    Jassal, Bijay, 2009-09-11.

    Editors

    Jassal, Bijay, 2009-08-21.

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    Reviewers

    He, Lei, 2009-11-12.

    The human SLC30A8 gene encodes the zinc transporter ZnT8 which is specifically expressed inpancreatic beta cells (Chimienti et al. 2005). Zinc is required for zinc-insulin crystallization withinsecretory vesicles of these cells. After glucose stimulation, large amounts of zinc are secretedlocally in the extracellular matrix together with insulin. It has been suggested that thisco-secreted zinc plays a role in islet cell paracrine and/or autocrine communication (Chimienti Fet al, 2006). Loss of function mutations in SLC30A8 are strongly protective against type 2diabetes, suggesting SLC20A8 inhibition as a therapeutic target in T2D prevention. (Flannick etal. 2014).

    References

    Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J,Van Lommel L, Grunwald D, Favier A, Seve M, "In vivo expression and functionalcharacterization of the zinc transporter ZnT8 in glucose-induced insulin secretion", J Cell Sci,119, 2006, 4199-206.

    Chimienti F, Favier A, Seve M, "ZnT-8, a pancreatic beta-cell-specific zinc transporter",Biometals, 18, 2005, 313-7.

    1.10 Insulin secretory granule translocates to cell cortex(BlackBoxEvent)

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    Authors

    May, B, 2008-05-13 13:18:27.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin)from the trans-golgi to the cellular cortex. Motor activity is provided by Dynamin-1 but thecomplex that connects the secretory granule to the Kinesin-1 is not yet fully known. The processis stimulated by intracellular calcium ions (Ca2+).

    References

    Rutter GA, Hill EV, "Insulin vesicle release: walk, kiss, pause ... then run", Physiology(Bethesda), 21, 2006, 189-96.

    Source reaction

    This reaction was inferred from the corresponding reaction "Insulin secretory granuletranslocates to cell cortex" in species Mus musculus.

    Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin)from the trans-golgi to the cellular cortex. Motor activity is provided by Kinesin-1 but the complexthat connects the secretory granule to the Kinesin-1 is not yet fully known. The process isstimulated by intracellular calcium ions (Ca2+).

    The following literature references support the source reaction:Meng YX, Wilson GW, Avery MC, Varden CH, Balczon R, "Suppression of the expression of apancreatic beta-cell form of the kinesin heavy chain by antisense oligonucleotides inhibits insulinsecretion from primary cultures of mouse beta-cells", Endocrinology, 138, 1997, 1979-87.

    Rutter GA, Hill EV, "Insulin vesicle release: walk, kiss, pause ... then run", Physiology

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    (Bethesda), 21, 2006, 189-96.

    Varadi A, Tsuboi T, Johnson-Cadwell LI, Allan VJ, Rutter GA, "Kinesin I and cytoplasmic dyneinorchestrate glucose-stimulated insulin-containing vesicle movements in clonal MIN6 beta-cells",

    Biochem Biophys Res Commun, 311, 2003, 272-82.

    1.11 Insulin secretory granules translocate across the corticalactin network to dock at plasma membrane (BlackBoxEvent)

    Authors

    May, B, 2008-05-13 13:18:27.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

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    Reviewers

    D'Eustachio, P, Matthews, L, Gillespie, ME, 2008-12-02 16:25:31.

    Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex ofuncertain composition. Myosin Va moves along the cortical actin network (actin at the peripheryof the cytoplasm), carrying the granules to the inner surface of the plasma membrane. A betacell contains about 10 000 secretory granules. Of these, about 1000 are docked at the innersurface of the plasma membrane and a subset of about 100 docked granules form the "readilyreleasable" pool (granules which are released within about 5 minutes of glucose stimulation).Docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretorygranule and EXOC4/Sec8 located at the plasma membrane. Additional components (EXOC1,EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex.

    References

    Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J,Schermerhorn T, Straub SG, Yajima H, Sharp GW, "Triggering and augmentation mechanisms,granule pools, and biphasic insulin secretion", Diabetes, 51, 2002, S83-90.

    Lang J, "Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrinesecretion", Eur J Biochem, 259, 1999, 3-17.

    Rutter GA, Hill EV, "Insulin vesicle release: walk, kiss, pause ... then run", Physiology(Bethesda), 21, 2006, 189-96.

    Tsuboi T, Ravier MA, Xie H, Ewart MA, Gould GW, Baldwin SA, Rutter GA, "Mammalian exocystcomplex is required for the docking step of insulin vesicle exocytosis", J Biol Chem, 280, 2005,25565-70.

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    Source reaction

    This reaction was inferred from the corresponding reaction "Insulin secretory granulestranslocate across the cortical actin network to dock at the plasma membrane" in species Mus

    musculus.

    Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex ofuncertain composition. Mysosin Va moves along the cortical actin network (actin at the peripheryof the cytoplasm), carrying the granules to the inner surface of the plasma membrane.

    The following literature references support the source reaction:

    Goehring AS, Pedroja BS, Hinke SA, Langeberg LK, Scott JD, "MyRIP anchors protein kinase Ato the exocyst complex", J Biol Chem, 282, 2007, 33155-67.

    Kasai K, Ohara-Imaizumi M, Takahashi N, Mizutani S, Zhao S, Kikuta T, Kasai H, Nagamatsu S,Gomi H, Izumi T, "Rab27a mediates the tight docking of insulin granules onto the plasmamembrane during glucose stimulation", J Clin Invest, 115, 2005, 388-96.

    Merrins MJ, Stuenkel EL, "Kinetics of Rab27a-dependent actions on vesicle docking and primingin pancreatic beta-cells", J Physiol, 586, 2008, 5367-81.

    Rutter GA, Hill EV, "Insulin vesicle release: walk, kiss, pause ... then run", Physiology(Bethesda), 21, 2006, 189-96.

    Varadi A, Tsuboi T, Rutter GA, "Myosin Va transports dense core secretory vesicles inpancreatic MIN6 beta-cells", Mol Biol Cell, 16, 2005, 2670-80.

    Yi Z, Yokota H, Torii S, Aoki T, Hosaka M, Zhao S, Takata K, Takeuchi T, Izumi T, "TheRab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-coregranules", Mol Cell Biol, 22, 2002, 1858-67.

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    1.12 Exocyst complex formation (BlackBoxEvent)

    Authors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    Editors

    May, B, Gopinathrao, G, 2008-11-19 19:22:37.

    A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at theinner surface of the plasma membrane and a subset of about 100 docked granules form the"readily releasable" pool (granules which are released within about 5 minutes of glucosestimulation). As inferred from rat MIN6 cells, docking occurs by interaction betweenEXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located atthe plasma membrane (Tsuboi et al. 2005). Additional components (EXOC1, EXOC2, EXOC5,EXOC6, EXOC7, EXOC8) form the Exocyst Complex. EXOC7 binds the plasma membrane(Matern et al. 2001).

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