Metabolomics

, Volume 10, Issue 5, pp 920–937 | Cite as

Role of the tumor suppressor IQGAP2 in metabolic homeostasis: possible link between diabetes and cancer

  • B. Vaitheesvaran
  • K. Hartil
  • A. Navare
  • C. Zheng
  • P. Ó Broin
  • A. Golden
  • C. Guha
  • W. N. Lee
  • I. J. Kurland
  • J. E. Bruce
Original Article

Abstract

Deficiency of IQGAP2, a scaffolding protein expressed primarily in liver leads to rearrangements of hepatic protein compartmentalization and altered regulation of enzyme functions predisposing development of hepatocellular carcinoma and diabetes. Employing a systems approach with proteomics, metabolomics and fluxes characterizations, we examined the effects of IQGAP2 deficient proteomic changes on cellular metabolism and the overall metabolic phenotype. Iqgap2/mice demonstrated metabolic inflexibility, fasting hyperglycemia and obesity. Such phenotypic characteristics were associated with aberrant hepatic regulations of glycolysis/gluconeogenesis, glycogenolysis, lipid homeostasis and futile cycling corroborated with corresponding proteomic changes in cytosolic and mitochondrial compartments. IQGAP2 deficiency also led to truncated TCA-cycle, increased anaplerosis, increased supply of acetyl-CoA for de novo lipogenesis, and increased mitochondrial methyl-donor metabolism necessary for nucleotides synthesis. Our results suggest that changes in metabolic networks in IQGAP2 deficiency create a hepatic environment of a ‘pre-diabetic’ phenotype and a predisposition to non-alcoholic fatty liver disease which has been linked to the development of hepatocellular carcinoma.

Keywords

IQGAP2 Metabolic inflexibility Hepatocellular carcinoma Diabetes Warburg-like Anaplerosis 

Supplementary material

11306_2014_639_MOESM1_ESM.jpg (766 kb)
Supplemental Figure S1Indirect Calorimetry: Oxygen Consumption (VO2) and activity for Iqgap2-/- and control were determined during the diurnal cycle and fasted to fed transitions. Day (light cycle) and night (dark cycle) 12 hours, (over)night fast – 15hrs, day re-fed - 5hrs in duration. n=8, (a) represents VO2 calculated normalizing measurements to total body mass, (b) represents VO2 calculated using lean body mass. (c) represents ambulatory activity determined simultaneously using an Opto-Varimetrix-3 sensor system. Consecutive adjacent infrared beam breaks in either the x- or y-axes were scored as an activity (total z counts). Activity was graphed by normalizing measurements to total body mass. Data are mean ±SEM. Error bars are represented only in one direction for clarity. Supplementary material 1 (JPEG 765 kb)
11306_2014_639_MOESM2_ESM.jpg (129 kb)
Supplemental Figure S2Bar graphs illustrating 18hr Fast and refed plasma levels of important amino acids for Iqgap2-/- and control mice. Data are mean ± SEM. * represents p<0.05 using Students T test comparisons for 18hr fast Iqgap2-/- and control mice. The refed aminoacid levels were comparable between the groups. F-phenylalanine, S – serine, I- Isoleucine, L- leucine, T- threonine, V-valine, M-methionine, E-glutamic acid, A-alanine, G-glycine. Supplementary material 2 (JPEG 128 kb)
11306_2014_639_MOESM3_ESM.jpg (478 kb)
Supplemental Figure S3Bar graphs illustrating stable isotope [U-13C6]-glucose (M+6) infusion studies a) represents hepatic glucose production calculated using isotope infusion rate and final M+6 glucose enrichments and is expressed as mg/kg/min. b) represents ‘F’ - sum of fraction mass isotopomers (M1/∑m+M2/∑m+M3/∑m) that recycled from the infused isotope [U-13C6]-glucose and contributed to Cori cycling. Data are mean ± SEM. ** represents p<0.001 using Students T test comparisons for 18hr fast Iqgap2-/- and control mice. Supplementary material 3 (JPEG 478 kb)
11306_2014_639_MOESM4_ESM.jpg (199 kb)
Supplemental Figure S4aImmunoblot analysis illustrating 18hr Fast and refed expressions of key metabolic proteins involved in hepatic anaplerotic (PC) and cataplerotic reactions (PEPCK, M2-PK is a unique isoform of pyruvate kinase expressed during hepatocarcinogenesis) for Iqgap2-/- and control mice. PC-pyruvate carboxylase, PEPCK-phosphoenol pyruvatec carboxy kinase, M2-PK- M2 isoform of pyruvate kinase.Supplementary material 4 (JPEG 199 kb)
11306_2014_639_MOESM5_ESM.jpg (306 kb)
Supplemental Figure S4bCritical proteins ( PC, PK and PEPCK) and loading control PCNA were quantifed using ImageJ software and are shown as bar graphs. Values were normalized to Control and are data±SEM . * represents p<0.05 for Iqgap2-/-against Control mice using Students’s Ttest. Supplementary material 5 (JPEG 305 kb)
11306_2014_639_MOESM6_ESM.jpg (239 kb)
Supplemental Figure S5Immunoblot analysis illustrating 18hr Fast and refed expressions of key metabolic proteins involved in lipid synthesis for Iqgap2-/- and control. FAS-fatty acid synthase, ACL- ATP citrate lyase, ACC – acetyl coA carboxylase, DGAT1 – diacylglycaerol acyl transferase 1, RAPTOR- regulatory-associated protein of mTOR.Supplementary material 6 (JPEG 239 kb)
11306_2014_639_MOESM7_ESM.jpg (163 kb)
Supplemental Figure S6Thin layer chromatography (TLC) analysis for lipids illustrating 18hr Fast and refed triglycerides levels in Iqgap2-/- and control mice. Supplementary material 7 (JPEG 163 kb)
11306_2014_639_MOESM8_ESM.jpg (337 kb)
Supplemental Figure S7Bar graphs illustrating 18hr Fast and refed hepatic levels for important antioxidant metabolites for Iqgap2-/- and control mice. Data are mean ± SEM. ** represents p<0.01 using Students T test. Supplementary material 8 (JPEG 337 kb)
11306_2014_639_MOESM9_ESM.jpg (229 kb)
Supplemental Figure S8Peptide-level MS1 integrated area calculation was performed on at least 5 peptides specific to pyruvate kinase R/L isoform. The stacked chromatograms of biological replicates of Fast Iqgap2-/- and control are shown with a chromatographic peak eluting around 61-63 minute, corresponding to peptide GSQVLVTVDPK. Integrated area under individual peak is highlighted. The inset mass spectrum corresponding to the chromatographic peak shows isotopic distribution of the singly charged protonated precursor ion of GSQVLVTVDPK at m/z 1142.64. The ratio of average peak area of fast Iqgap2-/- to the average peak area of fast control showed 2.6-fold increase for the peptide. Supplementary material 9 (JPEG 228 kb)
11306_2014_639_MOESM10_ESM.docx (24 kb)
Supplementary material 10 (DOCX 24 kb)
11306_2014_639_MOESM11_ESM.docx (12 kb)
Supplementary material 11 (DOCX 12 kb)
11306_2014_639_MOESM12_ESM.docx (17 kb)
Supplementary material 12 (DOCX 17 kb)
11306_2014_639_MOESM13_ESM.xlsx (27 kb)
Supplementary material 13 (XLSX 26 kb)
11306_2014_639_MOESM14_ESM.xlsx (12 kb)
Supplementary material 14 (XLSX 11 kb)
11306_2014_639_MOESM15_ESM.xlsx (15 kb)
Supplementary material 15 (XLSX 14 kb)
11306_2014_639_MOESM16_ESM.docx (14 kb)
Supplementary material 16 (DOCX 13 kb)
11306_2014_639_MOESM17_ESM.xlsx (24 kb)
Supplementary material 17 (XLSX 23 kb)

References

  1. An, S., et al. (2010). Microtubule-assisted mechanism for functional metabolic macromolecular complex formation. Proceedings of the National Academy of Sciences of the United States of America, 107(29), 12872–12876.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Atcheson, E., et al. (2011). IQ-motif selectivity in human IQGAP2 and IQGAP3: Binding of calmodulin and myosin essential light chain. Bioscience Reports, 31, 371–379.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Barron, J. T., Gu, L., & Parrillo, J. E. (1998). Malate–aspartate shuttle, cytoplasmic NADH redox potential, and energetics in vascular smooth muscle. Journal of Molecular and Cellular Cardiology, 30(8), 1571–1579.CrossRefPubMedGoogle Scholar
  4. Barry, R. M., & Gitai, Z. (2011). Self-assembling enzymes and the origins of the cytoskeleton. Current Opinion in Microbiology, 14(6), 704–711.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bindea, G., et al. (2009). ClueGO: A cytoscape plug-into decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics, 25(8), 1091–1093.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Brandt, D. T., & Grosse, R. (2007). Get to grips: Steering local actin dynamics with IQGAPs. EMBO Reports, 8(11), 1019–1023.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bratanova-Tochkova, T. K., et al. (2002). Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes, 51(Suppl 1), S83–S90.CrossRefPubMedGoogle Scholar
  8. Briggs, M. W., & Sacks, D. B. (2003). IQGAP proteins are integral components of cytoskeletal regulation. EMBO Reports, 4(6), 571–574.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Brill, S., et al. (1996). The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases. Molecular and Cellular Biology, 16(9), 4869–4878.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Brunengraber, D. Z., et al. (2003). Influence of diet on the modeling of adipose tissue triglycerides during growth. The American Journal of Physiology-Endocrinology and Metabolism, 285(4), E917–E925.CrossRefPubMedGoogle Scholar
  11. Burkart, A., et al. (2011). Adenylate kinase 2 links mitochondrial energy metabolism to the induction of the unfolded protein response. Journal of Biological Chemistry, 286(6), 4081–4089.CrossRefPubMedGoogle Scholar
  12. Chiariello, C. S., et al. (2012). Ablation of Iqgap2 protects from diet-induced hepatic steatosis due to impaired fatty acid uptake. Regulatory Peptides, 173(1–3), 36–46.CrossRefPubMedGoogle Scholar
  13. Dansen, T. B., & Wirtz, K. W. (2001). The peroxisome in oxidative stress. IUBMB Life, 51(4), 223–230.CrossRefPubMedGoogle Scholar
  14. DeBerardinis, R. J., et al. (2008). The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism, 7(1), 11–20.CrossRefPubMedGoogle Scholar
  15. Duncan, R. E., et al. (2007). Regulation of lipolysis in adipocytes. Annual Review of Nutrition, 27, 79–101.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Endemann, G., et al. (1982). Lipogenesis from ketone bodies in the isolated perfused rat liver. Evidence for the cytosolic activation of acetoacetate. Journal of Biological Chemistry, 257(7), 3434–3440.PubMedGoogle Scholar
  17. Erickson, J. W., Cerione, R. A., & Hart, M. J. (1997). Identification of an actin cytoskeletal complex that includes IQGAP and the Cdc42 GTPase. Journal of Biological Chemistry, 272(39), 24443–24447.CrossRefPubMedGoogle Scholar
  18. Fair, A. M., & Montgomery, K. (2009). Energy balance, physical activity, and cancer risk. Methods in Molecular Biology, 472, 57–88.CrossRefPubMedGoogle Scholar
  19. Galgani, J. E., Moro, C., & Ravussin, E. (2008). Metabolic flexibility and insulin resistance. The American Journal of Physiology-Endocrinology and Metabolism, 295(5), E1009–E1017.CrossRefPubMedGoogle Scholar
  20. Garcia-Ruiz, C., et al. (2013). Mitochondrial dysfunction in nonalcoholic fatty liver disease and insulin resistance: Cause or consequence? Free Radical Research, 47, 854–868.CrossRefPubMedGoogle Scholar
  21. Ghoshal, A. K., et al. (2005). Rapid measurement of plasma acylcarnitines by liquid chromatography–tandem mass spectrometry without derivatization. Clinica Chimica Acta; International Journal of Clinical Chemistry, 358(1–2), 104–112.CrossRefPubMedGoogle Scholar
  22. Gilibili, R. R., et al. (2011). Development and validation of a highly sensitive LC–MS/MS method for simultaneous quantitation of acetyl-CoA and malonyl-CoA in animal tissues. Biomedical Chromatography, 25(12), 1352–1359.CrossRefPubMedGoogle Scholar
  23. Goldberg, R. P., & Brunengraber, H. (1980). Contributions of cytosolic and mitochondrial acetyl-CoA syntheses to the activation of lipogenic acetate in rat liver. Advances in Experimental Medicine and Biology, 132, 413–418.PubMedGoogle Scholar
  24. Gong, B., Chen, Q., & Almasan, A. (1998). Ionizing radiation stimulates mitochondrial gene expression and activity. Radiation Research, 150(5), 505–512.CrossRefPubMedGoogle Scholar
  25. Griffin, N. M., et al. (2010). Label-free, normalized quantification of complex mass spectrometry data for proteomic analysis. Nature Biotechnology, 28(1), 83–89.CrossRefPubMedGoogle Scholar
  26. Gutierrez, J., et al. (2006). Free radicals, mitochondria, and oxidized lipids: The emerging role in signal transduction in vascular cells. Circulation Research, 99(9), 924–932.CrossRefPubMedGoogle Scholar
  27. Higashi, K., et al. (2011). Adipokine ganglioside GM2 activator protein stimulates insulin secretion. FEBS Letters, 585(16), 2587–2591.CrossRefPubMedGoogle Scholar
  28. Hinke, S. A., et al. (2012). Anchored phosphatases modulate glucose homeostasis. EMBO Journal, 31(20), 3991–4004.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Ingerson-Mahar, M., et al. (2010). The metabolic enzyme CTP synthase forms cytoskeletal filaments. Nature Cell Biology, 12(8), 739–746.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Jain, M., et al. (2012). Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science, 336(6084), 1040–1044.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Keller, A., et al. (2002). Empirical statistical model to estimate the accuracy of peptide identifications made by MS/MS and database search. Analytical Chemistry, 74(20), 5383–5392.CrossRefPubMedGoogle Scholar
  32. Kind, T., et al. (2009). FiehnLib: Mass spectral and retention index libraries for metabolomics based on quadrupole and time-of-flight gas chromatography/mass spectrometry. Analytical Chemistry, 81(24), 10038–10048.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kuroda, S., et al. (1996). Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1. Journal of Biological Chemistry, 271(38), 23363–23367.CrossRefPubMedGoogle Scholar
  34. Lee, W. N., Bergner, E. A., & Guo, Z. K. (1992). Mass isotopomer pattern and precursor-product relationship. Biological Mass Spectrometry, 21(2), 114–122.CrossRefPubMedGoogle Scholar
  35. Lee, W. N., Sorou, S., & Bergner, E. A. (1991). Glucose isotope, carbon recycling, and gluconeogenesis using [U-13C] glucose and mass isotopomer analysis. Biochemical Medicine and Metabolic Biology, 45(3), 298–309.CrossRefPubMedGoogle Scholar
  36. Lee, W. N., et al. (1994). In vivo measurement of fatty acids and cholesterol synthesis using D2O and mass isotopomer analysis. American Journal of Physiology, 266(5 Pt 1), E699–E708.PubMedGoogle Scholar
  37. Lee, Y. Y., et al. (2011). Subcellular tissue proteomics of hepatocellular carcinoma for molecular signature discovery. Journal of Proteome Research, 10(11), 5070–5083.CrossRefPubMedGoogle Scholar
  38. Li, J. M., et al. (2002). Effects of hydrogen peroxide on mitochondrial gene expression of intestinal epithelial cells. World Journal of Gastroenterology, 8(6), 1117–1122.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lloyd, M. D., et al. (2008). α-Methylacyl-CoA racemase—an ‘obscure’ metabolic enzyme takes centre stage. FEBS Journal, 275(6), 1089–1102.CrossRefPubMedGoogle Scholar
  40. Lloyd, M. D., et al. (2013). α-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S. Progress in Lipid Research, 52(2), 220–230.CrossRefPubMedGoogle Scholar
  41. Logue, J. S., et al. (2011). Anchored protein kinase A recruitment of active Rac GTPase. Journal of Biological Chemistry, 286(25), 22113–22121.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Lu, M., & Shyy, J. Y.-J. (2006). Sterol regulatory element-binding protein 1 is negatively modulated by PKA phosphorylation. American Journal of Physiology-Cell Physiology, 290(6), C1477–C1486.CrossRefPubMedGoogle Scholar
  43. Ma, D., et al. (2012). Inhibition of glycogen phosphorylation induces changes in cellular proteome and signaling pathways in MIA pancreatic cancer cells. Pancreas, 41(3), 397–408.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Mazurek, S., et al. (2002). Pyruvate kinase type M2: A crossroad in the tumor metabolome. British Journal of Nutrition, 87(Suppl 1), S23–S29.CrossRefPubMedGoogle Scholar
  45. McCallum, S. J., Erickson, J. W., & Cerione, R. A. (1998). Characterization of the association of the actin-binding protein, IQGAP, and activated Cdc42 with Golgi membranes. Journal of Biological Chemistry, 273(35), 22537–22544.CrossRefPubMedGoogle Scholar
  46. Ogawa, H., et al. (1998). Structure, function and physiological role of glycine N-methyltransferase. The International Journal of Biochemistry and Cell Biology, 30(1), 13–26.CrossRefPubMedGoogle Scholar
  47. Owen, O. E., Kalhan, S. C., & Hanson, R. W. (2002). The key role of anaplerosis and cataplerosis for citric acid cycle function. Journal of Biological Chemistry, 277(34), 30409–30412.CrossRefPubMedGoogle Scholar
  48. Park, C. Y., et al. (2008). Rapid and accurate peptide identification from tandem mass spectra. Journal of Proteome Research, 7(7), 3022–3027.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Pathmanathan, S., et al. (2011). The interaction of IQGAPs with calmodulin-like proteins. Biochemical Society Transactions, 39(2), 694–699.CrossRefPubMedGoogle Scholar
  50. Pilkis, S. J., & Granner, D. K. (1992). Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annual Review of Physiology, 54, 885–909.CrossRefPubMedGoogle Scholar
  51. Pisani, P. (2008). Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Archives of Physiology and Biochemistry, 114(1), 63–70.CrossRefPubMedGoogle Scholar
  52. Reaven, G. M., Hollenbeck, C. B., & Chen, Y. D. (1989). Relationship between glucose tolerance, insulin secretion, and insulin action in non-obese individuals with varying degrees of glucose tolerance. Diabetologia, 32(1), 52–55.CrossRefPubMedGoogle Scholar
  53. Roesch, K., et al. (2004). The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a–TIMM13 complex. Human Molecular Genetics, 13(18), 2101–2111.CrossRefPubMedGoogle Scholar
  54. Roessner, U., et al. (2000). Technical advance: Simultaneous analysis of metabolites in potato tuber by gas chromatography–mass spectrometry. The Plant Journal, 23(1), 131–142.CrossRefPubMedGoogle Scholar
  55. Sacks, D. B. (2006). The role of scaffold proteins in MEK/ERK signalling. Biochemical Society Transactions, 34(Pt 5), 833–836.CrossRefPubMedGoogle Scholar
  56. Schmidt, V. A. (2012). Watch the GAP: Emerging roles for IQ motif-containing GTPase-activating proteins IQGAPs in hepatocellular carcinoma. International Journal of Hepatology, 2012, 958673.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Schmidt, V. A., et al. (2003). IQGAP2 functions as a GTP-dependent effector protein in thrombin-induced platelet cytoskeletal reorganization. Blood, 101(8), 3021–3028.CrossRefPubMedGoogle Scholar
  58. Schmidt, V. A., et al. (2008). Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1 dependent. Molecular and Cellular Biology, 28(5), 1489–1502.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Scott, J. D., & Newton, A. C. (2012). Shedding light on local kinase activation. BMC Biology, 10, 61.CrossRefPubMedPubMedCentralGoogle Scholar
  60. Shannon, K. B. (2012). IQGAP family members in yeast, dictyostelium, and mammalian cells. Internation Journal of Cell Biology, 2012, 894817.Google Scholar
  61. Sipe, J. C., et al. (2010). Biomarkers of endocannabinoid system activation in severe obesity. PLoS ONE, 5(1), e8792.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Tailleux, A., et al. (2002). Apolipoprotein A-II, HDL metabolism and atherosclerosis. Atherosclerosis, 164(1), 1–13.CrossRefPubMedGoogle Scholar
  63. Tomlinson, S., Walker, S. W., & Brown, B. L. (1982). Calmodulin and insulin secretion. Diabetologia, 22(1), 1–5.CrossRefPubMedGoogle Scholar
  64. Vaitheesvaran, B., Leroith, D., & Kurland, I. J. (2010a). MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity. Diabetologia, 53, 2224–2232.CrossRefPubMedGoogle Scholar
  65. Vaitheesvaran, B., et al. (2010b). Advantages of dynamic “closed loop” stable isotope flux phenotyping over static “open loop” clamps in detecting silent genetic and dietary phenotypes. Metabolomics, 6(2), 180–190.CrossRefPubMedGoogle Scholar
  66. Vaitheesvaran, B., et al. (2012). Peripheral effects of FAAH deficiency on fuel and energy homeostasis: Role of dysregulated lysine acetylation. PLoS ONE, 7(3), e33717.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Valverde, I., et al. (1979). Calmodulin activation of adenylate cyclase in pancreatic islets. Science, 206(4415), 225–227.CrossRefPubMedGoogle Scholar
  68. van de Weijer, T., et al. (2013). Relationships between mitochondrial function and metabolic flexibility in type 2 diabetes mellitus. PLoS ONE, 8(2), e51648.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the warburg effect: The metabolic requirements of cell proliferation. Science, 324(5930), 1029–1033.CrossRefGoogle Scholar
  70. Vranic, M. (1992). Banting lecture: Glucose turnover. A key to understanding the pathogenesis of diabetes (indirect effects of insulin). Diabetes, 41(9), 1188–1206.CrossRefPubMedGoogle Scholar
  71. Wang, J., Tolan, D. R., & Pagliaro, L. (1997). Metabolic compartmentation in living cells: structural association of aldolase. Experimental Cell Research, 237(2), 445–451.CrossRefPubMedGoogle Scholar
  72. Wang, J., et al. (1996). The molecular nature of the F-actin binding activity of aldolase revealed with site-directed mutants. Journal of Biological Chemistry, 271(12), 6861–6865.CrossRefPubMedGoogle Scholar
  73. Wang, S., et al. (2007). IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth. Journal of Cell Science, 120(Pt 4), 567–577.CrossRefPubMedGoogle Scholar
  74. Weisbrod, C. R., et al. (2013). Performance evaluation of a dual linear ion trap-Fourier transform ion cyclotron resonance mass spectrometer for proteomics research. Journal of Proteomics, 88, 109–119.CrossRefPubMedPubMedCentralGoogle Scholar
  75. White, C. D., Brown, M. D., & Sacks, D. B. (2009). IQGAPs in cancer: A family of scaffold proteins underlying tumorigenesis. FEBS Letters, 583(12), 1817–1824.CrossRefPubMedPubMedCentralGoogle Scholar
  76. Wu, C., et al. (2009). BioGPS: An extensible and customizable portal for querying and organizing gene annotation resources. Genome Biology, 10(11), R130.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Xie, Y., et al. (2012). IQGAP2, a candidate tumour suppressor of prostate tumorigenesis. Biochimica et Biophysica Acta, 1822(6), 875–884.CrossRefPubMedGoogle Scholar
  78. Xu, J., et al. (2002). Peroxisome proliferator-activated receptor alpha (PPARalpha) influences substrate utilization for hepatic glucose production. Journal of Biological Chemistry, 277(52), 50237–50244.CrossRefPubMedGoogle Scholar
  79. Xu, J., et al. (2003). Determination of a glucose-dependent futile recycling rate constant from an intraperitoneal glucose tolerance test. Analytical Biochemistry, 315(2), 238–246.CrossRefPubMedGoogle Scholar
  80. Zhong, S., et al. (1994). Human ApoA-II inhibits the hydrolysis of HDL triglyceride and the decrease of HDL size induced by hypertriglyceridemia and cholesteryl ester transfer protein in transgenic mice. The Journal of Clinical Investigation, 94(6), 2457–2467.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • B. Vaitheesvaran
    • 1
  • K. Hartil
    • 1
  • A. Navare
    • 2
  • C. Zheng
    • 2
  • P. Ó Broin
    • 1
    • 4
  • A. Golden
    • 4
  • C. Guha
    • 3
  • W. N. Lee
    • 5
  • I. J. Kurland
    • 1
  • J. E. Bruce
    • 2
  1. 1.Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core FacilityAlbert Einstein College of MedicineBronxUSA
  2. 2.Department of Genome SciencesUniversity of WashingtonSeattleUSA
  3. 3.Department of Radiation OncologyAlbert Einstein College of MedicineBronxUSA
  4. 4.Department of Genetics., Division of Computational GeneticsAlbert Einstein College of MedicineBronxUSA
  5. 5.Department of Pediatrics, Division of Endocrinology and MetabolismUniversity of CaliforniaLos AngelesUSA

Personalised recommendations