Skip to main content
SpringerLink
Log in

Differential Regulation of IGF-1 and Insulin Signaling by GRKs

  • Protocol
  • First Online:
G Protein-Coupled Receptor Kinases

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Textbooks depict box-to-box signaling schematics downstream of G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), yet it is now widely accepted that cellular signaling is much more web-like than linear, and the nodes of crosstalk between pathways and receptors increase in complexity and intricacy with each additional study. A complex network involving bidirectional crosstalk between GPCRs and RTKs is emerging, and this phenomenon is commonly termed “transactivation.” In this process, RTKs or components of RTK pathways are utilized by GPCRs or, conversely, components of classical GPCRs such as G proteins, GRKs, and β-arrestins are recruited downstream of activated RTKs. This chapter aims to summarize the emerging evidence of RTKs utilizing GPCR components, thus blurring the boundaries we have given them. In particular, we will follow how all of the functional components of the GPCR system have been described for the insulin receptor (IR) and the insulin-like growth factor type 1 receptor (IGF-1R) and hence the rationale behind the development of a functional RTK/GPCR hybrid model. Given the IGF-1R’s important role in the development and maintenance of a malignant phenotype, GPCR components, such as the GRK/β-arrestin system, may yield important future targets in anti-IGF-1R therapeutics.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hupfeld CJ, Olefsky JM (2007) Regulation of receptor tyrosine kinase signaling by GRKs and beta-arrestins. Annu Rev Physiol 69:561–577

    Article  CAS  PubMed  Google Scholar 

  2. Aaronson SA (1991) Growth-factors and cancer. Science 254(5035):1146–1153

    Article  CAS  PubMed  Google Scholar 

  3. Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase-activity. Cell 61(2):203–212

    Article  CAS  PubMed  Google Scholar 

  4. Heldin CH (1995) Dimerization of cell-surface receptors in signal-transduction. Cell 80(2):213–223

    Article  CAS  PubMed  Google Scholar 

  5. Weiss A, Schlessinger J (1998) Switching signals on or off by receptor dimerization. Cell 94(3):277–280

    Article  CAS  PubMed  Google Scholar 

  6. Heldin CH, Ostman A (1996) Ligand-induced dimerization of growth factor receptors: variations on the theme. Cytokine Growth Factor Rev 7(1):3–10

    Article  CAS  PubMed  Google Scholar 

  7. Lemmon MA, Schlessinger J (1994) Regulation of signal-transduction and signal diversity by receptor oligomerization. Trends Biochem Sci 19(11):459–463

    Article  CAS  PubMed  Google Scholar 

  8. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Girnita L, Worrall C, Takahashi S, Seregard S, Girnita A (2014) Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation. Cell Mol Life Sci 71(13):2403–2427

    Article  CAS  PubMed  Google Scholar 

  10. Waterfield MD, Scrace GT, Whittle N, Stroobant P, Johnsson A, Wasteson A, Westermark B, Heldin CH, Huang JS, Deuel TF (1983) Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus. Nature 304(5921):35–39

    Article  CAS  PubMed  Google Scholar 

  11. Doolittle RF, Hunkapiller MW, Hood LE, Devare SG, Robbins KC, Aaronson SA, Antoniades HN (1983) Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor. Science 221(4607):275–277

    Article  CAS  PubMed  Google Scholar 

  12. Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD, Seeburg PH (1984) Human epidermal growth-factor receptor CDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma-cells. Nature 309(5967):418–425

    Article  CAS  PubMed  Google Scholar 

  13. Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26(22):3291–3310

    Article  CAS  PubMed  Google Scholar 

  14. Wong WM (1999) Trastuzumab: anti-HER2 antibody for treatment of metastatic breast cancer. Cancer Pract 7(1):48–50

    Article  CAS  PubMed  Google Scholar 

  15. Abdel-Rahman O (2015) Targeting platelet-derived growth factor (PDGF) signaling in gastrointestinal cancers: preclinical and clinical considerations. Tumor Biol 36(1):21–31

    Article  CAS  Google Scholar 

  16. Ashman LK, Griffith R (2013) Therapeutic targeting of c-KIT in cancer. Expert Opin Inv Drug 22(1):103–115

    Article  CAS  Google Scholar 

  17. Baserga R (1995) The insulin-like growth factor I receptor: a key to tumor growth? Cancer Res 55(2):249–252

    CAS  PubMed  Google Scholar 

  18. Jones JI, Clemmons DR (1995) Insulin-like growth-factors and their binding-proteins—biological actions. Endocr Rev 16(1):3–34

    CAS  PubMed  Google Scholar 

  19. Ullrich A, Gray A, Tam AW, Yangfeng T, Tsubokawa M, Collins C, Henzel W, Lebon T, Kathuria S, Chen E, Jacobs S, Francke U, Ramachandran J, Fujitayamaguchi Y (1986) Insulin-like growth factor-I receptor primary structure—comparison with insulin-receptor suggests structural determinants that define functional specificity. EMBO J 5(10):2503–2512

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Girnita A, Zheng H, Gronberg A, Girnita L, Stahle M (2012) Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. Oncogene 31(3):352–365

    Article  CAS  PubMed  Google Scholar 

  21. Raizada MK (1993) Insulin receptor-related receptor—an orphan with neurotrophic neuromodulatory potential. Endocrinology 133(1):1–2

    CAS  PubMed  Google Scholar 

  22. Soos MA, Whittaker J, Lammers R, Ullrich A, Siddle K (1990) Receptors for insulin and insulin-like growth factor-I can form hybrid dimers—characterization of hybrid receptors in transfected cells. Biochem J 270(2):383–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Favelyukis S, Till JH, Hubbard SR, Miller WT (2001) Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Biol 8(12):1058–1063

    Article  CAS  PubMed  Google Scholar 

  24. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor-I (Igf-1) and type-1 Igf receptor (Igf1r). Cell 75(1):59–72

    CAS  PubMed  Google Scholar 

  25. Kitamura T, Kahn CR, Accili E (2003) Insulin receptor knockout mice. Annu Rev Physiol 65:313–332

    Article  CAS  PubMed  Google Scholar 

  26. Efstratiadis A (1998) Genetics of mouse growth. Int J Dev Biol 42(7):955–976

    CAS  PubMed  Google Scholar 

  27. Sell C, Dumenil G, Deveaud C, Miura M, Coppola D, DeAngelis T, Rubin R, Efstratiadis A, Baserga R (1994) Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts. Mol Cell Biol 14(6):3604–3612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baserga R, Peruzzi F, Reiss K (2003) The IGF-1 receptor in cancer biology. Int J Cancer 107(6):873–877

    Article  CAS  PubMed  Google Scholar 

  29. Girnita A, All-Ericsson C, Economou MA, Astrom K, Axelson M, Seregard S, Larsson O, Girnita L (2006) The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells. Clin Cancer Res 12(4):1383–1391

    Article  CAS  PubMed  Google Scholar 

  30. Ulanet DB, Ludwig DL, Kahn CR, Hanahan D (2010) Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy. Proc Natl Acad Sci U S A 107(24):10791–10798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Soos MA, Siddle K (1989) Immunological relationships between receptors for insulin and insulin-like growth factor-I—evidence for structural heterogeneity of insulin-like growth factor-I receptors involving hybrids with insulin-receptors. Biochem J 263(2):553–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Moxham CP, Duronio V, Jacobs S (1989) Insulin-like growth factor-I receptor beta-subunit heterogeneity—evidence for hybrid tetramers composed of insulin-like growth factor-I and insulin-receptor heterodimers. J Biol Chem 264(22):13238–13244

    CAS  PubMed  Google Scholar 

  33. Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A (2002) Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 277(42):39684–39695

    Article  CAS  PubMed  Google Scholar 

  34. Belfiore A (2007) The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer. Curr Pharm Des 13(7):671–686

    Article  CAS  PubMed  Google Scholar 

  35. Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16(4):1103–1123

    Article  CAS  PubMed  Google Scholar 

  36. Girnita L, Wang M, Xie Y, Nilsson G, Dricu A, Wejde J, Larsson O (2000) Inhibition of N-linked glycosylation down-regulates insulin-like growth factor-1 receptor at the cell surface and kills Ewing’s sarcoma cells: therapeutic implications. Anticancer Drug Des 15(1):67–72

    CAS  PubMed  Google Scholar 

  37. Wang M, Xie Y, Girnita L, Nilsson G, Dricu A, Wejde J, Larsson O (1999) Regulatory role of mevalonate and N-linked glycosylation in proliferation and expression of the EWS/FLI-1 fusion protein in Ewing's sarcoma cells. Exp Cell Res 246(1):38–46

    Article  CAS  PubMed  Google Scholar 

  38. Girnita A, Girnita L, del Prete F, Bartolazzi A, Larsson O, Axelson M (2004) Cyclolignans as inhibitors of the insulin-like growth factor-1 receptor and malignant cell growth. Cancer Res 64(1):236–242

    Article  CAS  PubMed  Google Scholar 

  39. Baserga R (2005) The insulin-like growth factor-I receptor as a target for cancer therapy. Expert Opin Ther Targets 9(4):753–768

    Article  CAS  PubMed  Google Scholar 

  40. Gualberto A, Pollak M (2009) Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions. Oncogene 28(34):3009–3021

    Article  CAS  PubMed  Google Scholar 

  41. Furukawa J, Miyake H, Fujisawa M (2012) Antisense oligonucleotide targeting Insulin-like growth factor-1 receptor (IGF-1R) enhances paclitaxel sensitivity in a castrate-resistant and paclitaxel-resistant prostate cancer model. Eur Urol Suppl 11(1):E234

    Article  Google Scholar 

  42. Girnita L, Girnita A, Brodin B, Xie Y, Nilsson G, Dricu A, Lundeberg J, Wejde J, Bartolazzi A, Wiman KG, Larsson O (2000) Increased expression of insulin-like growth factor I receptor in malignant cells expressing aberrant p53: functional impact. Cancer Res 60(18):5278–5283

    CAS  PubMed  Google Scholar 

  43. Beauchamp MC, Yasmeen A, Knafo A, Gotlieb WH (2010) Targeting insulin and insulin-like growth factor pathways in epithelial ovarian cancer. J Oncol 2010:257058

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Crudden C, Ilic M, Suleymanova N, Worrall C, Girnita A, Girnita L (2015) The dichotomy of the Insulin-like growth factor 1 receptor: RTK and GPCR: friend or foe for cancer treatment? Growth Horm IGF Res 25(1):2–12

    Article  CAS  PubMed  Google Scholar 

  45. Natarajan K, Berk BC (2006) Crosstalk coregulation mechanisms of G protein-coupled receptors and receptor tyrosine kinases. Methods Mol Biol 332:51–77

    CAS  PubMed  Google Scholar 

  46. Luttrell L, Kilgour E, Larner J, Romero G (1990) A pertussis toxin-sensitive G-protein mediates some aspects of insulin action in BC3H-1 murine myocytes. J Biol Chem 265(28):16873–16879

    CAS  PubMed  Google Scholar 

  47. Heyworth CM, Grey AM, Wilson SR, Hanski E, Houslay MD (1986) The action of islet activating protein (pertussis toxin) on insulin ability to inhibit adenylate-cyclase and activate cyclic-AMP phosphodiesterases in hepatocytes. Biochem J 235(1):145–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rothenberg PL, Kahn CR (1988) Insulin inhibits pertussis toxin-catalyzed ADP-ribosylation of G-proteins—evidence for a novel interaction between insulin-receptors and G-proteins. J Biol Chem 263(30):15546–15552

    CAS  PubMed  Google Scholar 

  49. Imamura T, Vollenweider P, Egawa K, Clodi M, Ishibashi K, Nakashima N, Ugi S, Adams JW, Brown JH, Olefsky JM (1999) G alpha-q/11 protein plays a key role in insulin-induced glucose transport in 3T3-L1 adipocytes. Mol Cell Biol 19(10):6765–6774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Luttrell LM, van Biesen T, Hawes BE, Koch WJ, Touhara K, Lefkowitz RJ (1995) G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. J Biol Chem 270(28):16495–16498

    Article  CAS  PubMed  Google Scholar 

  51. Hallak H, Seiler AEM, Green JS, Ross BN, Rubin R (2000) Association of heterotrimeric G(i) with the insulin-like growth factor-I receptor—Release of G(beta gamma) subunits upon receptor activation. J Biol Chem 275(4):2255–2258

    Article  CAS  PubMed  Google Scholar 

  52. Dalle S, Ricketts W, Imamura T, Vollenweider P, Olefsky JM (2001) Insulin and insulin-like growth factor I receptors utilize different G protein signaling components. J Biol Chem 276(19):15688–15695

    Article  CAS  PubMed  Google Scholar 

  53. Waters C, Pyne S, Pyne NJ (2004) The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction. Semin Cell Dev Biol 15(3):309–323

    Article  CAS  PubMed  Google Scholar 

  54. Rakhit S, Pyne S, Pyne NJ (2001) Nerve growth factor stimulation of p42/p44 mitogen-activated protein kinase in PC12 cells: role of G(i/o), G protein-coupled receptor kinase 2, beta-arrestin I, and endocytic processing. Mol Pharmacol 60(1):63–70

    CAS  PubMed  Google Scholar 

  55. Pyne NJ, Pyne S (2011) Receptor tyrosine kinase-G-protein-coupled receptor signalling platforms: out of the shadow? Trends Pharmacol Sci 32(8):443–450

    Article  CAS  PubMed  Google Scholar 

  56. Lin FT, Daaka Y, Lefkowitz RJ (1998) beta-arrestins regulate mitogenic signaling and clathrin-mediated endocytosis of the insulin-like growth factor I receptor. J Biol Chem 273(48):31640–31643

    Article  CAS  PubMed  Google Scholar 

  57. Sehat B, Andersson S, Vasilcanu R, Girnita L, Larsson O (2007) Role of ubiquitination in IGF-1 receptor signaling and degradation. PLoS One 2(4):e340

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Vecchione A, Marchese A, Henry P, Rotin D, Morrione A (2003) The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol 23(9):3363–3372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Larsson O, Girnita A, Girnita L (2005) Role of insulin-like growth factor 1 receptor signalling in cancer. Br J Cancer 92(12):2097–2101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Girnita L, Girnita A, Larsson O (2003) Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A 100(14):8247–8252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O (2005) {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem 280(26):24412–24419

    Article  CAS  PubMed  Google Scholar 

  62. Lefkowitz RJ, Shenoy SK (2005) Transduction of receptor signals by beta-arrestins. Science 308(5721):512–517

    Article  CAS  PubMed  Google Scholar 

  63. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Vasilcanu D, Girnita A, Lefkowitz RJ, Larsson O (2007) Beta-arrestin and Mdm2 mediate IGF-1 receptor-stimulated ERK activation and cell cycle progression. J Biol Chem 282(15):11329–11338

    Article  CAS  PubMed  Google Scholar 

  64. Zheng H, Shen H, Oprea I, Worrall C, Stefanescu R, Girnita A, Girnita L (2012) beta-Arrestin-biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor-targeting antibodies in Ewing’s sarcoma. Proc Natl Acad Sci U S A 109(50):20620–20625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Vasilcanu R, Vasilcanu D, Sehat B, Yin S, Girnita A, Axelson M, Girnita L (2008) Insulin-like growth factor type-I receptor-dependent phosphorylation of extracellular signal-regulated kinase 1/2 but not Akt (protein kinase B) can be induced by picropodophyllin. Mol Pharmacol 73(3):930–939

    Article  CAS  PubMed  Google Scholar 

  66. Zheng H, Worrall C, Shen H, Issad T, Seregard S, Girnita A, Girnita L (2012) Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor. Proc Natl Acad Sci U S A 109(18):7055–7060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chow JC, Condorelli G, Smith RJ (1998) Insulin-like growth factor-1 receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. J Biol Chem 273(8):4672–4680

    Article  CAS  PubMed  Google Scholar 

  68. Morrison DK, Davis RJ (2003) Regulation of map kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol 19:91–118

    Article  CAS  PubMed  Google Scholar 

  69. McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ (2000) Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290(5496):1574–1577

    Article  CAS  PubMed  Google Scholar 

  70. Sacks DB (2006) The role of scaffold proteins in MEK/ERK signalling. Biochem Soc Trans 34:833–836

    Article  CAS  PubMed  Google Scholar 

  71. Povsic TJ, Kohout TA, Lefkowitz RJ (2003) beta-arrestin1 mediates insulin-like growth factor 1 (IGF-1) activation of phosphatidylinositol 3-kinase (PI3K) and anti-apoptosis. J Biol Chem 278(51):51334–51339

    Article  CAS  PubMed  Google Scholar 

  72. Zhande R, Mitchell JJ, Wu J, Sun XJ (2002) Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1. Mol Cell Biol 22(4):1016–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rui LY, Yuan MS, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277(44):42394–42398

    Article  CAS  PubMed  Google Scholar 

  74. Dalle S, Imamura T, Rose DW, Worrall DS, Ugi S, Hupfeld CJ, Olefsky JM (2002) Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1. Mol Cell Biol 22(17):6272–6285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Luan B, Zhao J, Wu HY, Duan BY, Shu GW, Wang XY, Li DS, Jia WP, Kang JH, Pei G (2009) Deficiency of a beta-arrestin-2 signal complex contributes to insulin resistance. Nature 457(7233):1146–1149

    Article  CAS  PubMed  Google Scholar 

  76. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ (2006) beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem 281(2):1261–1273

    Article  CAS  PubMed  Google Scholar 

  77. Lefkowitz RJ (2004) Historical review: a brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol Sci 25(8):413–422

    Article  CAS  PubMed  Google Scholar 

  78. Shenoy SK, Lefkowitz RJ (2003) Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling. Biochem J 375(Pt 3):503–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK (2007) Beta-arrestins and cell signaling. Annu Rev Physiol 69:483–510

    Article  CAS  PubMed  Google Scholar 

  80. Usui I, Imamura T, Huang J, Satoh H, Olefsky JM (2003) Cdc42 is a rho GTPase family member that can mediate insulin signaling to glucose transport in 3T3-L1 adipocytes. J Biol Chem 278(16):13765–13774

    Article  CAS  PubMed  Google Scholar 

  81. Usui I, Imamura T, Satoh H, Huang J, Babendure JL, Hupfeld CJ, Olefsky JM (2004) GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. EMBO J 23(14):2821–2829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gao JX, Li JL, Ma L (2005) Regulation of EGF-induced ERK/MAPK activation and EGFR internalization by G protein-coupled receptor kinase 2. Acta Biochim Biophys Sin 37(8):525–531

    Article  CAS  PubMed  Google Scholar 

  83. Alderton F, Rakhit S, Kong KC, Palmer T, Sambi B, Pyne S, Pyne NJ (2001) Tethering of the platelet-derived growth factor ss receptor to G-protein-coupled receptors—a novel platform for integrative signaling by these receptor classes in mammalian cells. J Biol Chem 276(30):28578–28585

    Article  CAS  PubMed  Google Scholar 

  84. Hobson JP, Rosenfeldt HM, Barak LS, Olivera A, Poulton S, Caron MG, Milstien S, Spiegel S (2001) Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291(5509):1800–1803

    Article  CAS  PubMed  Google Scholar 

  85. Freedman NJ, Kim LK, Murray JP, Exum ST, Brian L, Wu JH, Peppel K (2002) Phosphorylation of the platelet-derived growth factor receptor-beta and epidermal growth factor receptor by G protein-coupled receptor kinase-2—mechanisms for selectivity of desensitization. J Biol Chem 277(50):48261–48269

    Article  CAS  PubMed  Google Scholar 

  86. Penela P, Murga C, Ribas C, Lafarga V, Mayor F (2010) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br J Pharmacol 160(4):821–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross J Jr, Lefkowitz RJ, Caron MG, Giros B (1996) Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci U S A 93(23):12974–12979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Matkovich SJ, Marreez Y, Diwan A, Odley AM, Koch WJ, Schwartz RJ, Brunskill EW, Dorn GW (2006) Cardiac-specific ablation of GRK2 re-defines its roles in heart development and beta-adrenergic signaling. Circulation 114(18):159

    Google Scholar 

  89. Jiang X, Yang P, Ma L (2009) Kinase activity-independent regulation of cyclin pathway by GRK2 is essential for zebrafish early development. Proc Natl Acad Sci U S A 106(25):10183–10188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wan KF, Sambi BS, Tate R, Waters C, Pyne NJ (2003) The inhibitory gamma subunit of the type 6 retinal cGMP phosphodiesterase functions to link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase by epidermal growth factor. J Biol Chem 278(20):18658–18663

    Article  CAS  PubMed  Google Scholar 

  91. Bliziotes M, Gunness M, Zhang XW, Nissenson R, Wiren K (2000) Reduced G-protein-coupled-receptor kinase 2 activity results in impairment of osteoblast function. Bone 27(3):367–373

    Article  CAS  PubMed  Google Scholar 

  92. Metaye T, Gibelin H, Perdrisot R, Kraimps JL (2005) Pathophysiological roles of G-protein-coupled receptor kinases. Cell Signal 17(8):917–928

    Article  CAS  PubMed  Google Scholar 

  93. King DW, Steinmetz R, Wagoner HA, Hannon TS, Chen LY, Eugster EA, Pescovitz OH (2003) Differential expression of GRK isoforms in nonmalignant and malignant human granulosa cells. Endocrine 22(2):135–141

    Article  CAS  PubMed  Google Scholar 

  94. Metaye T, Menet E, Guilhot J, Kraimps JL (2002) Expression and activity of G protein-coupled receptor kinases in differentiated thyroid carcinoma. J Clin Endocr Metab 87(7):3279–3286

    Article  CAS  PubMed  Google Scholar 

  95. Bookout AL, Finney AE, Guo RS, Peppel K, Koch WJ, Daaka Y (2003) Targeting G beta gamma signaling to inhibit prostate tumor formation and growth. J Biol Chem 278(39):37569–37573

    Article  CAS  PubMed  Google Scholar 

  96. Ho J, Cocolakis E, Dumas VM, Posner BI, Laporte PA, Lebrun JJ (2005) The G protein-coupled receptor kinase-2 is a TGF beta-inducible antagonist of TGF beta signal transduction. EMBO J 24(18):3247–3258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Metaye T, Levillain P, Kraimps JL, Perdrisot R (2008) Immunohistochemical detection, regulation and antiproliferative function of G-protein-coupled receptor kinase 2 in thyroid carcinomas. J Endocrinol 198(1):101–110

    Article  CAS  PubMed  Google Scholar 

  98. Penela P, Nogues L, Mayor F Jr (2014) Role of G protein-coupled receptor kinases in cell migration. Curr Opin Cell Biol 27:10–17

    Article  CAS  PubMed  Google Scholar 

  99. Penela P, Ribas C, Aymerich I, Eijkelkamp N, Barreiro O, Heijnen CJ, Kavelaars A, Sanchez-Madrid F, Mayor F (2008) G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J 27(8):1206–1218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Vroon A, Heijnen CJ, Lombardi MS, Cobelens PM, Mayor F, Caron MG, Kavelaars A (2004) Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4. J Leukocyte Biol 75(5):901–909

    Article  CAS  PubMed  Google Scholar 

  101. Vroon A, Heijnen CJ, Kavelaars A (2006) GRKs and arrestins: regulators of migration and inflammation. J Leukocyte Biol 80(6):1214–1221

    Article  CAS  PubMed  Google Scholar 

  102. Conway AM, Rakhit S, Pyne S, Pyne NJ (1999) Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase. Biochem J 337(Pt 2):171–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang BH, Ho V, Farrell GC (2001) Specific involvement of G(alpha i2) with epidermal growth factor receptor signaling in rat hepatocytes, and the inhibitory effect of chronic ethanol. Biochem Pharmacol 61(8):1021–1027

    Article  CAS  PubMed  Google Scholar 

  104. Piiper A, StryjekKaminska D, Zeuzem S (1997) Epidermal growth factor activates phospholipase C-gamma(1) via G(i1-2) proteins in isolated pancreatic acinar membranes. Am J Physiol 272(5):G1276–G1284

    CAS  PubMed  Google Scholar 

  105. Zeng HY, Zhao DZ, Yang SP, Datta K, Mukhopadhyay D (2003) Heterotrimeric G alpha(q)/G alpha(11) proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J Biol Chem 278(23):20738–20745

    Article  CAS  PubMed  Google Scholar 

  106. Gavard J, Gutkind JS (2006) VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8(11):1223–1234

    Article  CAS  PubMed  Google Scholar 

  107. Rieck PW, Cholidis S, Hartmann C (2001) Intracellular signaling pathway of FGF-2-modulated corneal endothelial cell migration during wound healing in vitro. Exp Eye Res 73(5):639–650

    Article  CAS  PubMed  Google Scholar 

  108. Sa G, Fox PL (1994) Basic fibroblast growth factor-stimulated endothelial-cell movement is mediated by a pertussis-toxin-sensitive pathway regulating phospholipase-A(2) activity. J Biol Chem 269(5):3219–3225

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research support for Leonard Girnita’s group: Swedish Research Council, Swedish Cancer Society, Children Cancer Society, Crown Princess Margareta’s Foundation for the Visually Impaired, Welander Finsen Foundation, King Gustaf V Jubilee Foundation, Stockholm Cancer Society, the Stockholm County, and Karolinska Institutet.

Author information

Authors and Affiliations

  1. Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, Stockholm, 17176, Sweden

    Leonard Girnita M.D., Ph.D., Ada Girnita & Caitrin Crudden

Authors
  1. Leonard Girnita M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ada Girnita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caitrin Crudden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonard Girnita M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Pharmacology, Vanderbilt University , NASHVILLE, Tennessee, USA

    Vsevolod V. Gurevich

  2. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

    Eugenia V. Gurevich

  3. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    John J.G. Tesmer

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Girnita, L., Girnita, A., Crudden, C. (2016). Differential Regulation of IGF-1 and Insulin Signaling by GRKs. In: Gurevich, V., Gurevich, E., Tesmer, J. (eds) G Protein-Coupled Receptor Kinases. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3798-1_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3798-1_7

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3796-7

  • Online ISBN: 978-1-4939-3798-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation