Emerging Roles of Small GTPases in Islet β-Cell Function
Tóm tắt
Several small guanosine triphosphatases (GTPases) from the Ras protein superfamily regulate glucose-stimulated insulin secretion in the pancreatic islet β-cell. The Rho family GTPases Cdc42 and Rac1 are primarily involved in relaying key signals in several cellular functions, including vesicle trafficking, plasma membrane homeostasis, and cytoskeletal dynamics. They orchestrate specific changes at each spatiotemporal region within the β-cell by coordinating with signal transducers, guanine nucleotide exchange factors (GEFs), GTPase-activating factors (GAPs), and their effectors. The Arf family of small GTPases is involved in vesicular trafficking (exocytosis and endocytosis) and actin cytoskeletal dynamics. Rab-GTPases regulate pre-exocytotic and late endocytic membrane trafficking events in β-cells. Several additional functions for small GTPases include regulating transcription factor activity and mitochondrial dynamics. Importantly, defects in several of these GTPases have been found associated with type 2 diabetes (T2D) etiology. The purpose of this review is to systematically denote the identities and molecular mechanistic steps in the glucose-stimulated insulin secretion pathway that leads to the normal release of insulin. We will also note newly identified defects in these GTPases and their corresponding regulatory factors (e.g., GDP dissociation inhibitors (GDIs), GEFs, and GAPs) in the pancreatic β-cells, which contribute to the dysregulation of metabolism and the development of T2D.
Từ khóa
Tài liệu tham khảo
Cerasi, 1975, Mechanisms of glucose stimulated insulin secretion in health and in diabetes: Some re-evaluations and proposals, Diabetologia, 11, 1, 10.1007/BF00422811
Cerasi, 1975, Potentiation of insulin release by glucose in man. II. Role of the insulin response, and enhancement of stimuli other than glucose, Acta Endocrinol., 79, 502
Chadt, 2020, Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease, Pflug. Arch. Eur. J. Physiol., 472, 1273, 10.1007/s00424-020-02417-x
Berger, 2020, Glucose transporters in pancreatic islets, Pflug. Arch. Eur. J. Physiol., 472, 1249, 10.1007/s00424-020-02383-4
Ashcroft, 1994, Stimulus-secretion coupling in pancreatic beta cells, J. Cell. Biochem., 55, 54, 10.1002/jcb.240550007
Doliba, 2012, Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics, Am. J. Physiol. Endocrinol. Metab., 302, E87, 10.1152/ajpendo.00218.2011
Gembal, 1993, Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells, J. Clin. Investig., 91, 871, 10.1172/JCI116308
Matschinsky, 1996, Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm, Diabetes, 45, 223, 10.2337/diab.45.2.223
Prentki, 2020, Lipid-associated metabolic signalling networks in pancreatic beta cell function, Diabetologia, 63, 10, 10.1007/s00125-019-04976-w
Rorsman, 2013, Regulation of insulin secretion in human pancreatic islets, Annu. Rev. Physiol., 75, 155, 10.1146/annurev-physiol-030212-183754
Seino, 2011, Dynamics of insulin secretion and the clinical implications for obesity and diabetes, J. Clin. Investig., 121, 2118, 10.1172/JCI45680
Henquin, 2017, Pharmacological approach to understanding the control of insulin secretion in human islets, Diabetes Obes. Metab., 19, 1061, 10.1111/dom.12887
Henquin, 2006, In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: Pattern and role of cytoplasmic Ca2+ and amplification signals in beta-cells, Diabetes, 55, 441, 10.2337/diabetes.55.02.06.db05-1051
2021, Insulin granule biogenesis and exocytosis, Cell. Mol. Life Sci. CMLS, 78, 1957, 10.1007/s00018-020-03688-4
Arous, 2015, The skeleton in the closet: Actin cytoskeletal remodeling in beta-cell function, Am. J. Physiol. Endocrinol. Metab., 309, E611, 10.1152/ajpendo.00268.2015
Sekine, 1994, Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogenase in pancreatic beta-cells. Potential role in nutrient sensing, J. Biol. Chem., 269, 4895, 10.1016/S0021-9258(17)37629-9
McCommis, 2016, An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion, Mol. Metab., 5, 602, 10.1016/j.molmet.2016.06.016
Meredith, 1995, Cytosolic biosynthesis of GTP and ATP in normal rat pancreatic islets, Biochim. Biophys. Acta, 1266, 16, 10.1016/0167-4889(94)00235-7
Meredith, 1995, Evidence of a role for GTP in the potentiation of Ca(2+)-induced insulin secretion by glucose in intact rat islets, J. Clin. Investig., 96, 811, 10.1172/JCI118127
Metz, 1993, Small elevations of glucose concentration redirect and amplify the synthesis of guanosine 5’-triphosphate in rat islets, J. Clin. Investig., 92, 872, 10.1172/JCI116662
Stark, 2009, Phosphoenolpyruvate cycling via mitochondrial phosphoenolpyruvate carboxykinase links anaplerosis and mitochondrial GTP with insulin secretion, J. Biol. Chem., 284, 26578, 10.1074/jbc.M109.011775
Kibbey, 2007, Mitochondrial GTP regulates glucose-stimulated insulin secretion, Cell Metab., 5, 253, 10.1016/j.cmet.2007.02.008
Jesinkey, 2019, Mitochondrial GTP Links Nutrient Sensing to beta Cell Health, Mitochondrial Morphology, and Insulin Secretion Independent of OxPhos, Cell Rep., 28, 759, 10.1016/j.celrep.2019.06.058
Metz, 1992, Selective inhibitors of GTP synthesis impede exocytotic insulin release from intact rat islets, J. Biol. Chem., 267, 12517, 10.1016/S0021-9258(18)42308-3
Ottaway, 1981, Succinic thiokinase and metabolic control, Int. J. Biochem., 13, 401, 10.1016/0020-711X(81)90111-7
Smith, 1974, Regulation of mitochondrial alpha-ketoglutarate metabolism by product inhibition at alpha-ketoglutarate dehydrogenase, J. Biol. Chem., 249, 1497, 10.1016/S0021-9258(19)42910-4
Drahota, 1983, Phosphoenolpyruvate shuttle—Transport of energy from mitochondria to cytosol, FEBS Lett., 157, 347, 10.1016/0014-5793(83)80573-0
Mawla, 2017, Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets, Cell Metab., 25, 911, 10.1016/j.cmet.2017.03.017
Saeedi, 2019, Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition, Diabetes Res. Clin. Pract., 157, 107843, 10.1016/j.diabres.2019.107843
Holman, 2020, beta-cell secretory dysfunction: A key cause of type 2 diabetes, Lancet. Diabetes Endocrinol., 8, 370, 10.1016/S2213-8587(20)30119-4
Hudish, 2019, beta Cell dysfunction during progression of metabolic syndrome to type 2 diabetes, J. Clin. Investig., 129, 4001, 10.1172/JCI129188
Magkos, 2020, Diet and exercise in the prevention and treatment of type 2 diabetes mellitus, Nat. Rev. Endocrinol., 16, 545, 10.1038/s41574-020-0381-5
Krentz, 2020, Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics, Nat. Rev. Endocrinol., 16, 202, 10.1038/s41574-020-0325-0
Ashcroft, 2012, Diabetes mellitus and the beta cell: The last ten years, Cell, 148, 1160, 10.1016/j.cell.2012.02.010
Bray, 2018, The Science of Obesity Management: An Endocrine Society Scientific Statement, Endocr. Rev., 39, 79, 10.1210/er.2017-00253
Salunkhe, 2018, Novel approaches to restore beta cell function in prediabetes and type 2 diabetes, Diabetologia, 61, 1895, 10.1007/s00125-018-4658-3
Gandasi, 2018, Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes, Cell Metab., 27, 470, 10.1016/j.cmet.2017.12.017
Rojas, 2012, The Ras protein superfamily: Evolutionary tree and role of conserved amino acids, J. Cell Biol., 196, 189, 10.1083/jcb.201103008
Liu, 2017, A thirty-year quest for a role of R-Ras in cancer: From an oncogene to a multitasking GTPase, Cancer Lett., 403, 59, 10.1016/j.canlet.2017.06.003
Qu, 2019, The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases, Front. Mol. Neurosci., 12, 121, 10.3389/fnmol.2019.00121
Vetter, 2001, The guanine nucleotide-binding switch in three dimensions, Science, 294, 1299, 10.1126/science.1062023
Bourne, 1991, The GTPase superfamily: Conserved structure and molecular mechanism, Nature, 349, 117, 10.1038/349117a0
Karnoub, 2008, Ras oncogenes: Split personalities, Nat. Rev. Mol. Cell Biol., 9, 517, 10.1038/nrm2438
Toma-Fukai, S., and Shimizu, T. (2019). Structural Insights into the Regulation Mechanism of Small GTPases by GEFs. Molecules, 24.
Nevins, 2003, Glucose regulates the cortical actin network through modulation of Cdc42 cycling to stimulate insulin secretion, Am. J. Physiol. Cell Physiol., 285, C698, 10.1152/ajpcell.00093.2003
Nevins, 2005, A direct interaction between Cdc42 and vesicle-associated membrane protein 2 regulates SNARE-dependent insulin exocytosis, J. Biol. Chem., 280, 1944, 10.1074/jbc.M409528200
Nevins, 2006, Caveolin-1 functions as a novel Cdc42 guanine nucleotide dissociation inhibitor in pancreatic beta-cells, J. Biol. Chem., 281, 18961, 10.1074/jbc.M603604200
Regazzi, 1992, The small GTP-binding proteins in the cytosol of insulin-secreting cells are complexed to GDP dissociation inhibitor proteins, J. Biol. Chem., 267, 17512, 10.1016/S0021-9258(19)37072-3
Sugimoto, 2011, RhoB loss prevents streptozotocin-induced diabetes and ameliorates diabetic complications in mice, Am. J. Pathol., 178, 245, 10.1016/j.ajpath.2010.11.040
Liu, 2014, Involvement of RhoA/ROCK in insulin secretion of pancreatic beta-cells in 3D culture, Cell Tissue Res., 358, 359, 10.1007/s00441-014-1961-2
Kowluru, 1997, Evidence for differential roles of the Rho subfamily of GTP-binding proteins in glucose- and calcium-induced insulin secretion from pancreatic beta cells, Biochem. Pharmacol., 54, 1097, 10.1016/S0006-2952(97)00314-6
Li, 2004, Novel regulation by Rac1 of glucose- and forskolin-induced insulin secretion in INS-1 beta-cells, Am. J. Physiol. Endocrinol. Metab., 286, E818, 10.1152/ajpendo.00307.2003
Kowluru, 1994, Subcellular localization and kinetic characterization of guanine nucleotide binding proteins in normal rat and human pancreatic islets and transformed beta cells, Biochim. Biophys. Acta, 1222, 348, 10.1016/0167-4889(94)90040-X
Daniel, 2002, A link between Cdc42 and syntaxin is involved in mastoparan-stimulated insulin release, Biochemistry, 41, 9663, 10.1021/bi025604p
Kowluru, 2003, Novel roles for the rho subfamily of GTP-binding proteins in succinate-induced insulin secretion from betaTC3 cells: Further evidence in support of the succinate mechanism of insulin release, Endocr. Res., 29, 363, 10.1081/ERC-120025043
Seabra, 2001, Evolution of the Rab family of small GTP-binding proteins, J. Mol. Biol., 313, 889, 10.1006/jmbi.2001.5072
Segev, 2001, Ypt and Rab GTPases: Insight into functions through novel interactions, Curr. Opin. Cell Biol., 13, 500, 10.1016/S0955-0674(00)00242-8
Jackson, 2014, Arfs at a glance, J. Cell Sci., 127, 4103
Chavrier, 2006, ARF proteins: Roles in membrane traffic and beyond, Nat. Rev. Mol. Cell Biol., 7, 347, 10.1038/nrm1910
Benarroch, 2019, Nucleocytoplasmic transport: Mechanisms and involvement in neurodegenerative disease, Neurology, 92, 757, 10.1212/WNL.0000000000007305
Veluthakal, 2007, Dominant-negative alpha-subunit of farnesyl- and geranyltransferase inhibits glucose-stimulated, but not KCl-stimulated, insulin secretion in INS 832/13 cells, Diabetes, 56, 204, 10.2337/db06-0668
Veluthakal, 2009, Regulatory roles for Tiam1, a guanine nucleotide exchange factor for Rac1, in glucose-stimulated insulin secretion in pancreatic beta-cells, Biochem. Pharmacol., 77, 101, 10.1016/j.bcp.2008.09.021
Wang, 2007, Glucose-stimulated Cdc42 signaling is essential for the second phase of insulin secretion, J. Biol. Chem., 282, 9536, 10.1074/jbc.M610553200
Kowluru, 1996, Glucose- and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure beta cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion, J. Clin. Investig., 98, 540, 10.1172/JCI118822
Yi, 2002, The Rab27a/granuphilin complex regulates the exocytosis of insulin-containing dense-core granules, Mol. Cell Biol., 22, 1858, 10.1128/MCB.22.6.1858-1867.2002
Ljubicic, S., Bezzi, P., Brajkovic, S., Nesca, V., Guay, C., Ohbayashi, N., Fukuda, M., Abderrhamani, A., and Regazzi, R. (2013). The GTPase Rab37 Participates in the Control of Insulin Exocytosis. PLoS ONE, 8.
Matsunaga, 2017, Rab2a and Rab27a cooperatively regulate the transition from granule maturation to exocytosis through the dual effector Noc2, J. Cell Sci., 130, 541, 10.1242/jcs.195479
Regazzi, 1992, Characterization of small-molecular-mass guanine-nucleotide-binding regulatory proteins in insulin-secreting cells and PC12 cells, Eur. J. Biochem., 208, 729, 10.1111/j.1432-1033.1992.tb17241.x
Shibasaki, 2007, Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP, Proc. Natl. Acad. Sci. USA, 104, 19333, 10.1073/pnas.0707054104
Schmidt, 2002, Guanine nucleotide exchange factors for Rho GTPases: Turning on the switch, Genes Dev., 16, 1587, 10.1101/gad.1003302
Bernards, 2004, GAP control: Regulating the regulators of small GTPases, Trends Cell Biol., 14, 377, 10.1016/j.tcb.2004.05.003
Repasky, 2004, Renewing the conspiracy theory debate: Does Raf function alone to mediate Ras oncogenesis?, Trends Cell Biol., 14, 639, 10.1016/j.tcb.2004.09.014
Konstantinopoulos, 2007, Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets, Nat. Rev. Drug Discov., 6, 541, 10.1038/nrd2221
Wang, 2016, Protein prenylation: Unique fats make their mark on biology, Nat. Rev. Mol. Cell Biol., 17, 110, 10.1038/nrm.2015.11
Seabra, 1991, Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit, Cell, 65, 429, 10.1016/0092-8674(91)90460-G
Reid, 2004, Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity, J. Mol. Biol., 343, 417, 10.1016/j.jmb.2004.08.056
Goalstone, 2010, Glucose activates prenyltransferases in pancreatic islet beta-cells, Biochem. Biophys. Res. Commun., 391, 895, 10.1016/j.bbrc.2009.11.159
Seabra, 1992, Rab geranylgeranyl transferase. A multisubunit enzyme that prenylates GTP-binding proteins terminating in Cys-X-Cys or Cys-Cys, J. Biol. Chem., 267, 14497, 10.1016/S0021-9258(19)49740-8
Arora, 2012, Rab-geranylgeranyl transferase regulates glucose-stimulated insulin secretion from pancreatic beta cells, Islets, 4, 354, 10.4161/isl.22538
Wu, 2007, Interaction analysis of prenylated Rab GTPase with Rab escort protein and GDP dissociation inhibitor explains the need for both regulators, Proc. Natl. Acad. Sci. USA, 104, 12294, 10.1073/pnas.0701817104
Shinde, 2018, Post translational modifications of Rab GTPases, Small GTPases, 9, 49, 10.1080/21541248.2017.1299270
Metz, 1993, Modulation of insulin secretion from normal rat islets by inhibitors of the post-translational modifications of GTP-binding proteins, Biochem. J., 295, 31, 10.1042/bj2950031
Li, 1993, Blockade of mevalonate production by lovastatin attenuates bombesin and vasopressin potentiation of nutrient-induced insulin secretion in HIT-T15 cells. Probable involvement of small GTP-binding proteins, Biochem. J., 289, 379, 10.1042/bj2890379
Amin, 2002, Inhibition of glucose- and calcium-induced insulin secretion from betaTC3 cells by novel inhibitors of protein isoprenylation, J. Pharm. Exp., 303, 82, 10.1124/jpet.102.036160
Eisenberg, 1998, Cholesterol lowering in the management of coronary artery disease: The clinical implications of recent trials, Am. J. Med., 104, 2S, 10.1016/S0002-9343(98)00038-2
Cederberg, 2015, Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: A 6 year follow-up study of the METSIM cohort, Diabetologia, 58, 1109, 10.1007/s00125-015-3528-5
Sattar, 2010, Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials, Lancet, 375, 735, 10.1016/S0140-6736(09)61965-6
Preiss, 2011, Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: A meta-analysis, JAMA, 305, 2556, 10.1001/jama.2011.860
Rajpathak, 2009, Statin therapy and risk of developing type 2 diabetes: A meta-analysis, Diabetes Care, 32, 1924, 10.2337/dc09-0738
Ridker, 2008, Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein, N. Engl. J. Med., 359, 2195, 10.1056/NEJMoa0807646
Shepherd, 2002, Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial, Lancet, 360, 1623, 10.1016/S0140-6736(02)11600-X
Crandall, 2017, Statin use and risk of developing diabetes: Results from the Diabetes Prevention Program, BMJ. Open Diabetes Res. Care, 5, e000438, 10.1136/bmjdrc-2017-000438
Kowluru, 2010, Small G proteins in islet beta-cell function, Endocr. Rev., 31, 52, 10.1210/er.2009-0022
Kowluru, 2016, A lack of ‘glue’ misplaces Rab27A to cause islet dysfunction in diabetes, J. Pathol., 238, 375, 10.1002/path.4671
Jiang, 2016, GGPPS-mediated Rab27A geranylgeranylation regulates beta cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation, J. Pathol., 238, 109, 10.1002/path.4652
Wang, 2010, Differential phosphorylation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion, J. Biol. Chem., 285, 6186, 10.1074/jbc.M109.072421
Carlsson, 1980, Actin filament formation in pancreatic beta-cells during glucose stimulation of insulin secretion, FEBS Lett., 117, 299, 10.1016/0014-5793(80)80966-5
Varadi, 2005, Myosin Va transports dense core secretory vesicles in pancreatic MIN6 beta-cells, Mol. Biol. Cell, 16, 2670, 10.1091/mbc.e04-11-1001
Orci, 1972, Pancreatic beta-cell web: Its possible role in insulin secretion, Science, 175, 1128, 10.1126/science.175.4026.1128
Kepner, 2011, Cool-1/betaPIX functions as a guanine nucleotide exchange factor in the cycling of Cdc42 to regulate insulin secretion, Am. J. Physiol. Endocrinol. Metab., 301, E1072, 10.1152/ajpendo.00312.2011
Wehinger, 2015, Phosphorylation of caveolin-1 on tyrosine-14 induced by ROS enhances palmitate-induced death of beta-pancreatic cells, Biochim. Biophys. Acta, 1852, 693, 10.1016/j.bbadis.2014.12.021
Zeng, 2018, Caveolin-1 deficiency protects pancreatic beta cells against palmitate-induced dysfunction and apoptosis, Cell Signal., 47, 65, 10.1016/j.cellsig.2018.03.013
Lillo Urzua, P., Nunez Murillo, O., Castro-Sepulveda, M., Torres-Quintana, M.A., Lladser Caldera, A., Quest, A.F.G., Espinoza Robles, C., Llanos Vidal, P., and Wehinger, S. (2020). Loss of Caveolin-1 Is Associated with a Decrease in Beta Cell Death in Mice on a High Fat Diet. Int. J. Mol. Sci., 21.
He, 2020, Specific deletion of CDC42 in pancreatic beta cells attenuates glucose-induced insulin expression and secretion in mice, Mol. Cell Endocrinol., 518, 111004, 10.1016/j.mce.2020.111004
Duan, 2019, miR-29a Negatively Affects Glucose-Stimulated Insulin Secretion and MIN6 Cell Proliferation via Cdc42/beta-Catenin Signaling, Int. J. Endocrinol., 2019, 5219782, 10.1155/2019/5219782
Sun, 2021, Expression of miRNA-29 in Pancreatic beta Cells Promotes Inflammation and Diabetes via TRAF3, Cell Rep., 34, 108576, 10.1016/j.celrep.2020.108576
Ursino, 2020, ABCA12 regulates insulin secretion from beta-cells, EMBO Rep., 21, e48692, 10.15252/embr.201948692
Veluthakal, 2018, Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets, Diabetes, 67, 1999, 10.2337/db17-1174
Asahara, 2013, Ras-related C3 botulinum toxin substrate 1 (RAC1) regulates glucose-stimulated insulin secretion via modulation of F-actin, Diabetologia, 56, 1088, 10.1007/s00125-013-2849-5
Greiner, T.U., Kesavan, G., Stahlberg, A., and Semb, H. (2009). Rac1 regulates pancreatic islet morphogenesis. BMC Dev. Biol., 9.
Veluthakal, 2015, VAV2, a guanine nucleotide exchange factor for Rac1, regulates glucose-stimulated insulin secretion in pancreatic beta cells, Diabetologia, 58, 2573, 10.1007/s00125-015-3707-4
Gao, 2004, Rational design and characterization of a Rac GTPase-specific small molecule inhibitor, Proc. Natl. Acad. Sci. USA, 101, 7618, 10.1073/pnas.0307512101
Crespo, 1997, Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product, Nature, 385, 169, 10.1038/385169a0
Schuebel, 1998, Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2, EMBO J., 17, 6608, 10.1093/emboj/17.22.6608
Han, 1997, Lck regulates Vav activation of members of the Rho family of GTPases, Mol. Cell Biol., 17, 1346, 10.1128/MCB.17.3.1346
Michel, 1998, Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells, J. Biol. Chem., 273, 31932, 10.1074/jbc.273.48.31932
Deckert, 1996, Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product, Immunity, 5, 591, 10.1016/S1074-7613(00)80273-3
Bustelo, 1992, Tyrosine phosphorylation of the vav proto-oncogene product in activated B cells, Science, 256, 1196, 10.1126/science.256.5060.1196
Bustelo, 1992, Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates, Nature, 356, 68, 10.1038/356068a0
Margolis, 1992, Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs, Nature, 356, 71, 10.1038/356071a0
Yoder, 2014, YES, a Src family kinase, is a proximal glucose-specific activator of cell division cycle control protein 42 (Cdc42) in pancreatic islet beta cells, J. Biol. Chem., 289, 11476, 10.1074/jbc.M114.559328
Kowluru, 2005, Rho guanosine diphosphate-dissociation inhibitor plays a negative modulatory role in glucose-stimulated insulin secretion, Diabetes, 54, 3523, 10.2337/diabetes.54.12.3523
Thamilselvan, 2021, Paradoxical regulation of glucose-induced Rac1 activation and insulin secretion by RhoGDIbeta in pancreatic beta-cells, Small GTPases, 12, 114, 10.1080/21541248.2019.1635403
Hodge, 2016, Regulating Rho GTPases and their regulators, Nat. Rev. Mol. Cell Biol., 17, 496, 10.1038/nrm.2016.67
Boulter, 2011, The ’invisible hand’: Regulation of RHO GTPases by RHOGDIs, Nat. Rev. Mol. Cell Biol., 12, 493, 10.1038/nrm3153
DerMardirossian, 2006, Phosphorylation of RhoGDI by Src regulates Rho GTPase binding and cytosol-membrane cycling, Mol. Biol. Cell, 17, 4760, 10.1091/mbc.e06-06-0533
Dovas, 2010, Serine 34 phosphorylation of rho guanine dissociation inhibitor (RhoGDIalpha) links signaling from conventional protein kinase C to RhoGTPase in cell adhesion, J. Biol. Chem., 285, 23296, 10.1074/jbc.M109.098129
Sabbatini, M.E., and Williams, J.A. (2013). Cholecystokinin-mediated RhoGDI phosphorylation via PKCalpha promotes both RhoA and Rac1 signaling. PLoS ONE, 8.
DerMardirossian, 2006, Phosphorylation of RhoGDI by p21-activated kinase 1, Methods Enzym., 406, 80, 10.1016/S0076-6879(06)06007-1
Fei, F., Kweon, S.M., Haataja, L., De Sepulveda, P., Groffen, J., and Heisterkamp, N. (2010). The Fer tyrosine kinase regulates interactions of Rho GDP-Dissociation Inhibitor alpha with the small GTPase Rac. BMC Biochem., 11.
Oishi, 2012, Regulation of RhoA signaling by the cAMP-dependent phosphorylation of RhoGDIalpha, J. Biol. Chem., 287, 38705, 10.1074/jbc.M112.401547
Tkachenko, 2011, Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells, Nat. Cell Biol., 13, 660, 10.1038/ncb2231
Cho, 2018, Protein phosphatase 1B dephosphorylates Rho guanine nucleotide dissociation inhibitor 1 and suppresses cancer cell migration and invasion, Cancer Lett., 417, 141, 10.1016/j.canlet.2018.01.002
Cho, H.J., Kim, J.T., Baek, K.E., Kim, B.Y., and Lee, H.G. (2019). Regulation of Rho GTPases by RhoGDIs in Human Cancers. Cells, 8.
Schmidt, 2007, Phospholipase D signaling: Orchestration by PIP2 and small GTPases, Naunyn Schmiedebergs Arch. Pharm., 374, 399, 10.1007/s00210-007-0131-4
Chuang, 1993, Biologically active lipids are regulators of Rac.GDI complexation, J. Biol. Chem., 268, 26206, 10.1016/S0021-9258(19)74301-4
Faure, 1999, Phosphoinositide-dependent activation of Rho A involves partial opening of the RhoA/Rho-GDI complex, Eur. J. Biochem., 262, 879, 10.1046/j.1432-1327.1999.00458.x
Fleming, 1997, Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C, J. Biol. Chem., 272, 33105, 10.1074/jbc.272.52.33105
McDonald, 2007, Biologically active lipids promote trafficking and membrane association of Rac1 in insulin-secreting INS 832/13 cells, Am. J. Physiol. Cell Physiol., 292, C1216, 10.1152/ajpcell.00467.2006
Alderson, 2004, Integrins regulate Rac targeting by internalization of membrane domains, Science, 303, 839, 10.1126/science.1092571
Kiosses, 2002, Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI, Nat. Cell Biol., 4, 232, 10.1038/ncb759
Tiedge, 1997, Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells, Diabetes, 46, 1733, 10.2337/diab.46.11.1733
Matsuoka, 1997, Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells, J. Clin. Investig., 99, 144, 10.1172/JCI119126
Sakai, 2003, Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells, Biochem. Biophys. Res. Commun., 300, 216, 10.1016/S0006-291X(02)02832-2
Kaneto, 2001, Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress, J. Biol. Chem., 276, 31099, 10.1074/jbc.M104115200
Oliveira, 2003, Pancreatic beta-cells express phagocyte-like NAD(P)H oxidase, Diabetes, 52, 1457, 10.2337/diabetes.52.6.1457
Morgan, 2007, Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of a phagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line, Diabetologia, 50, 359, 10.1007/s00125-006-0462-6
Rastogi, 2016, NOX Activation by Subunit Interaction and Underlying Mechanisms in Disease, Front. Cell. Neurosci., 10, 301
Abo, 1991, Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1, Nature, 353, 668, 10.1038/353668a0
Syed, 2011, Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: Role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet, Diabetes, 60, 2843, 10.2337/db11-0809
Syed, 2011, Phagocyte-like NADPH oxidase generates ROS in INS 832/13 cells and rat islets: Role of protein prenylation, Am. J. Physiol. Regul. Integr. Comp. Physiol., 300, R756, 10.1152/ajpregu.00786.2010
Sidarala, 2015, Phagocyte-like NADPH oxidase (Nox2) promotes activation of p38MAPK in pancreatic beta-cells under glucotoxic conditions: Evidence for a requisite role of Ras-related C3 botulinum toxin substrate 1 (Rac1), Biochem. Pharmacol., 95, 301, 10.1016/j.bcp.2015.04.001
Veluthakal, 2016, NSC23766, a Known Inhibitor of Tiam1-Rac1 Signaling Module, Prevents the Onset of Type 1 Diabetes in the NOD Mouse Model, Cell Physiol. Biochem., 39, 760, 10.1159/000445666
Baidwan, 2017, Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet beta-cells: Reversal of such metabolic defects by metformin, Apoptosis, 22, 1380, 10.1007/s10495-017-1409-8
Gaschet, 1999, Distribution of ARF6 between membrane and cytosol is regulated by its GTPase cycle, J. Biol. Chem., 274, 20040, 10.1074/jbc.274.28.20040
Honda, 1999, Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation, Cell, 99, 521, 10.1016/S0092-8674(00)81540-8
Shome, 1998, ADP-ribosylation factor proteins mediate agonist-induced activation of phospholipase D, J. Biol. Chem., 273, 30836, 10.1074/jbc.273.46.30836
Cockcroft, 2001, Inositol lipids as spatial regulators of membrane traffic, J. Membr. Biol., 180, 187, 10.1007/s002320010069
Lawrence, 2003, ADP-ribosylation factor 6 regulates insulin secretion through plasma membrane phosphatidylinositol 4,5-bisphosphate, Proc. Natl. Acad. Sci. USA, 100, 13320, 10.1073/pnas.2232129100
Jayaram, 2011, Arf nucleotide binding site opener [ARNO] promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion in INS 832/13 beta-cells and rat islets, Biochem. Pharmacol., 81, 1016, 10.1016/j.bcp.2011.01.006
Aramata, 2005, Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1, Biochim. Biophys. Acta, 1730, 41, 10.1016/j.bbaexp.2005.05.009
Docherty, 2005, Relative contribution of PDX-1, MafA and E47/beta2 to the regulation of the human insulin promoter, Biochem. J., 389, 813, 10.1042/BJ20041891
Ma, 2010, Role of phospholipase D1 in glucose-induced insulin secretion in pancreatic Beta cells, Exp. Mol. Med., 42, 456, 10.3858/emm.2010.42.6.047
Stenmark, 2009, Rab GTPases as coordinators of vesicle traffic, Nat. Rev. Mol. Cell Biol., 10, 513, 10.1038/nrm2728
Zerial, 2014, Rab proteins and the compartmentalization of the endosomal system, Cold Spring Harb. Perspect. Biol., 6, a022616, 10.1101/cshperspect.a022616
Pfeffer, 2013, Rab GTPase regulation of membrane identity, Curr. Opin. Cell Biol., 25, 414, 10.1016/j.ceb.2013.04.002
Chavrier, 1991, Hypervariable C-terminal domain of rab proteins acts as a targeting signal, Nature, 353, 769, 10.1038/353769a0
Novick, 1993, The role of GTP-binding proteins in transport along the exocytic pathway, Annu. Rev. Cell Biol., 9, 575, 10.1146/annurev.cb.09.110193.003043
Merrins, 2008, Kinetics of Rab27a-dependent actions on vesicle docking and priming in pancreatic beta-cells, J. Physiol., 586, 5367, 10.1113/jphysiol.2008.158477
Haddad, 2001, Defective granule exocytosis in Rab27a-deficient lymphocytes from Ashen mice, J. Cell Biol., 152, 835, 10.1083/jcb.152.4.835
Kasai, 2005, Rab27a mediates the tight docking of insulin granules onto the plasma membrane during glucose stimulation, J. Clin. Investig., 115, 388, 10.1172/JCI200522955
Regazzi, 1996, Expression, localization and functional role of small GTPases of the Rab3 family in insulin-secreting cells, J. Cell Sci., 109, 2265, 10.1242/jcs.109.9.2265
Coppola, 1999, Disruption of Rab3-calmodulin interaction, but not other effector interactions, prevents Rab3 inhibition of exocytosis, EMBO J., 18, 5885, 10.1093/emboj/18.21.5885
Zhao, 2002, Involvement of Rab27b in the regulated secretion of pituitary hormones, Endocrinology, 143, 1817, 10.1210/endo.143.5.8823
Lam, 2010, Mapping dynamic protein interactions to insulin secretory granule behavior with TIRF-FRET, Biophys. J., 99, 1311, 10.1016/j.bpj.2010.06.014
Waselle, 2003, Involvement of the Rab27 binding protein Slac2c/MyRIP in insulin exocytosis, Mol. Biol. Cell, 14, 4103, 10.1091/mbc.e03-01-0022
Yaekura, 2003, Insulin secretory deficiency and glucose intolerance in Rab3A null mice, J. Biol. Chem., 278, 9715, 10.1074/jbc.M211352200
Coppola, 2002, Pancreatic beta-cell protein granuphilin binds Rab3 and Munc-18 and controls exocytosis, Mol. Biol. Cell, 13, 1906, 10.1091/mbc.02-02-0025
Kuroda, 2002, Synaptotagmin-like protein 5: A novel Rab27A effector with C-terminal tandem C2 domains, Biochem. Biophys. Res. Commun., 293, 899, 10.1016/S0006-291X(02)00320-0
Kuroda, 2002, The Slp homology domain of synaptotagmin-like proteins 1-4 and Slac2 functions as a novel Rab27A binding domain, J. Biol. Chem., 277, 9212, 10.1074/jbc.M112414200
Stermann, 2018, Deletion of the RabGAP TBC1D1 Leads to Enhanced Insulin Secretion and Fatty Acid Oxidation in Islets From Male Mice, Endocrinology, 159, 1748, 10.1210/en.2018-00087
Orci, 1973, Exocytosis-endocytosis coupling in the pancreatic beta cell, Science, 181, 561, 10.1126/science.181.4099.561
MacDonald, 2007, The ins and outs of secretion from pancreatic beta-cells: Control of single-vesicle exo- and endocytosis, Physiology, 22, 113, 10.1152/physiol.00047.2006
Cousin, 2000, Synaptic vesicle endocytosis: Calcium works overtime in the nerve terminal, Mol. Neurobiol., 22, 115, 10.1385/MN:22:1-3:115
Ryan, 2006, A pre-synaptic to-do list for coupling exocytosis to endocytosis, Curr. Opin. Cell Biol., 18, 416, 10.1016/j.ceb.2006.06.013
Takei, 2005, Regulatory mechanisms of dynamin-dependent endocytosis, J. Biochem., 137, 243, 10.1093/jb/mvi052
Yamaoka, 2016, PI3K regulates endocytosis after insulin secretion by mediating signaling crosstalk between Arf6 and Rab27a, J. Cell Sci., 129, 637, 10.1242/jcs.180141
Paleotti, 2005, The small G-protein Arf6GTP recruits the AP-2 adaptor complex to membranes, J. Biol. Chem., 280, 21661, 10.1074/jbc.M503099200
Wang, 2013, The Rab27a effector exophilin7 promotes fusion of secretory granules that have not been docked to the plasma membrane, Mol. Biol. Cell, 24, 319, 10.1091/mbc.e12-04-0265
Yamaoka, 2015, Interplay between Rab27a effectors in pancreatic beta-cells, World J. Diabetes, 6, 508, 10.4239/wjd.v6.i3.508
Pasheva, 1998, Identification of a specific effector of the small GTP-binding protein Rap2, Eur. J. Biochem., 252, 290, 10.1046/j.1432-1327.1998.2520290.x
Holz, 2004, Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell, Diabetes, 53, 5, 10.2337/diabetes.53.1.5
Kang, 2001, cAMP-regulated guanine nucleotide exchange factor II (Epac2) mediates Ca2+-induced Ca2+ release in INS-1 pancreatic beta-cells, J. Physiol., 536, 375, 10.1111/j.1469-7793.2001.0375c.xd
McAvoy, 2009, Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology, Proc. Natl. Acad. Sci. USA, 106, 3531, 10.1073/pnas.0813263106
Takahashi, 2013, Protein kinase A-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration, J. Biol. Chem., 288, 27712, 10.1074/jbc.M113.466904
Leech, 2010, Epac2-dependent rap1 activation and the control of islet insulin secretion by glucagon-like peptide-1, Vitam. Horm., 84, 279, 10.1016/B978-0-12-381517-0.00010-2
Nakazaki, 2002, cAMP-activated protein kinase-independent potentiation of insulin secretion by cAMP is impaired in SUR1 null islets, Diabetes, 51, 3440, 10.2337/diabetes.51.12.3440
Kelly, 2010, Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation, J. Biol. Chem., 285, 15777, 10.1074/jbc.M109.069112
Zhang, 2019, GLP-1 Receptor in Pancreatic alpha-Cells Regulates Glucagon Secretion in a Glucose-Dependent Bidirectional Manner, Diabetes, 68, 34, 10.2337/db18-0317
Richards, 2014, Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model, Diabetes, 63, 1224, 10.2337/db13-1440
Moens, 1996, Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells, Diabetes, 45, 257, 10.2337/diab.45.2.257
Drucker, 2006, The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes, Lancet, 368, 1696, 10.1016/S0140-6736(06)69705-5
Gheni, 2014, Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion, Cell Rep., 9, 661, 10.1016/j.celrep.2014.09.030
Dzhura, 2010, Epac2-dependent mobilization of intracellular Ca(2)+ by glucagon-like peptide-1 receptor agonist exendin-4 is disrupted in beta-cells of phospholipase C-epsilon knockout mice, J. Physiol., 588, 4871, 10.1113/jphysiol.2010.198424
Dzhura, 2011, Phospholipase C-epsilon links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans, Islets, 3, 121, 10.4161/isl.3.3.15507
Chundru, S. (2020). Novel Regulatory Roles Of Rhog And Iqgaps In Pancreatic Islet Beta Cell Function. [Ph.D. Thesis, Wayne State University].
Mercader, J.M., Puiggros, M., Segre, A.V., Planet, E., Sorianello, E., Sebastian, D., Rodriguez-Cuenca, S., Ribas, V., Bonas-Guarch, S., and Draghici, S. (2012). Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems. PLoS Genet., 8.
Thamilselvan, 2020, P-Rex1 Mediates Glucose-Stimulated Rac1 Activation and Insulin Secretion in Pancreatic beta-Cells, Cell Physiol. Biochem., 54, 1218, 10.33594/000000310
Lewis, 2010, Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans, Genomics, 96, 211, 10.1016/j.ygeno.2010.07.006
Moltke, 2014, A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes, Nature, 512, 190, 10.1038/nature13425
Bouzakri, 2008, Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic beta-cells, Diabetes, 57, 1195, 10.2337/db07-1469
Ndiaye, 2017, Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion, Mol. Metab., 6, 459, 10.1016/j.molmet.2017.03.011