Regulation of IGF-I Receptor Signaling in Tumor Cells

R. O'Connor

doi:10.1055/s-2004-814166

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2003; 35(11/12): 771-777
DOI: 10.1055/s-2004-814166

Review

Regulation of IGF-I Receptor Signaling in Tumor Cells

R. O'Connor¹

¹Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, National University of Ireland, Cork, Ireland

Abstract

Signals from the IGF-IR and other members of the IR family contribute to the growth, survival, adhesion, and motility of tumor cells. These signals are initiated through recruitment of adapter proteins including the IRS family and Shc proteins, and are mediated through the PI3-kinase, mitogen activated protein (MAP) kinase and stress-activated protein kinase (SAPK) pathways. Regulation of signaling responses from the IGF-IR involves the actions of regulatory adapter proteins including RACK1 and Grb10 that recruit or sequester cytoplasmic proteins, and the actions of phosphatases including tyrosine PTP-1B, PTEN, and PP2A. This review focuses on the signaling pathways that are activated by the IGF-IR in tumor cells, the mechanisms of regulation of these pathways by adapter proteins and phosphatases, and how modulation of IGF-IR signaling could contribute to cancer progression.

Key words

IGF-1 Receptor - Phosphatases - RACK1 - Signal transduction

Full Text

References

1 Sciacca L. et al . Signaling differences from the A and B isoforms of the insulin receptor (IR) in 32D cells in the presence or absence of IR substrate-1. Endocrinology. 2003; 144 2650-2658
2 Pandini G. et al . Differential gene expression induced by insulin and Insulin-like Growth Factor-II through the insulin receptor isoform A. J Biol Chem. 2003; 278 42178-42189
3 Bailyes E M. et al . Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J. 1997; 327 209-215
4 Frisch S M, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol. 1994; 124 619-626
5 Valentinis B, Reiss K, Baserga R. Insulin-like growth factor-I-mediated survival from anoikis: role of cell aggregation and focal adhesion kinase. J Cell Physiol. 1998; 176 648-657
6 Almeida E A. et al . Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase. J Cell Biol. 2000; 149 741-754
7 Desbois-Mouthon C. et al . Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene. 2001; 20 252-259
8 Harada H, Andersen J S, Mann M, Terada N, Korsmeyer S J. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA. 2001; 98 9666-9670
9 Heron-Milhavet L, Karas M, Goldsmith C M, Baum B J, LeRoith D. Insulin-like growth factor-I (IGF-I) receptor activation rescues UV-damaged cells through a p38 signaling pathway. Potential role of the IGF-I receptor in DNA repair. J Biol Chem. 2001; 276 18 185-18 192
10 Krause D, Lyons A, Fennelly C, O’Connor R. Transient activation of Jun N-terminal kinases and protection from apoptosis by the insulin-like growth factor I receptor can be suppressed by dicumarol. J Biol Chem. 2001; 276 19 244-19 252
11 Zhou X M, Liu Y, Payne G, Lutz R J, Chittenden T. Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem. 2000; 275 25 046-25 051
12 Andre F. et al . Protein kinases C-gamma and -delta are involved in insulin-like growth factor I-induced migration of colonic epithelial cells. Gastroenterology. 1999; 116 64-77
13 Dong C. et al . JNK is required for effector T-cell function but not for T-cell activation. Nature. 2000; 405 91-94
14 Rodrigues G A, Park M, Schlessinger J. Activation of the JNK pathway is essential for transformation by the Met oncogene. Embo J. 1997; 16 2634-2645
15 Roulston A, Reinhard C, Amiri P, Williams L T. Early activation of c-Jun N-terminal kinase and p38 kinase regulate cell survival in response to tumor necrosis factor alpha. J Biol Chem. 1998; 273 10 232-10 239
16 Monno S, Newman M V, Cook M, Lowe W L, Jr. Insulin-like growth factor I activates c-Jun N-terminal kinase in MCF-7 breast cancer cells. Endocrinology. 2000; 141 544-550
17 De Smaele E. et al . Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature. 2001; 414 308-313
18 Hess P, Pihan G, Sawyers C L, Flavell R A, Davis R J. Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat Genet. 2002; 32 201-205
19 She Q B, Chen N, Bode A M, Flavell R A, Dong Z. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 2002; 62 1343-1348
20 Kennedy N J. et al . Suppression of Ras-stimulated transformation by the JNK signal transduction pathway. Genes Dev. 2003; 17 629-637
21 Lee Y H, Giraud J, Davis R J, White M F. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem. 2003; 278 2896-2902
22 Mamay C L, Mingo-Sion A M, Wolf D M, Molina M D, van den Berg C L. An inhibitory function for JNK in the regulation of IGF-I signaling in breast cancer. Oncogene. 2003; 22 602-614
23 Hess P, Pihan G, Sawyers C L, Flavell R A, Davis R J. Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat Genet. 2002; 32 201-205
24 Javelaud D, Laboureau J, Gabison E, Verrecchia F, Mauviel A. Disruption of basal JNK activity differentially affects key fibroblast functions important for wound healing. J Biol Chem. 2003; 278 24 624-24 628
25 Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M. Regulation of Raf-Akt Cross-talk. J Biol Chem. 2002; 277 31 099-31 106
26 Satyamoorthy K. et al . Constitutive mitogen-activated protein kinase activation in melanoma is mediated by both BRAF mutations and autocrine growth factor stimulation. Cancer Res. 2003; 63 756-759
27 Huang S. et al . Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1). Mol Cell. 2003; 11 1491-1501
28 Horton L E. et al . p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation. Oncogene. 2002; 21 5325-5334
29 Gustafson T A, He W, Craparo A, Schaub C D, O’Neill T J. Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain. Mol Cell Biol. 1995; 15 2500-2508
30 Nolan M K. et al . Differential roles of IRS-1 and SHC signaling pathways in breast cancer cells. Int J Cancer. 1997; 72 828-834
31 Chow J C, Condorelli G, Smith R J. Insulin-like growth factor-I receptor internalization regulates signaling via the Shc/mitogen-activated protein kinase pathway, but not the insulin receptor substrate-1 pathway. J Biol Chem. 1998; 273 4672-4680
32 Mauro L. et al . SHC-alpha5beta1 integrin interactions regulate breast cancer cell adhesion and motility. Exp Cell Res. 1999; 252 439-448
33 Reiss K. et al . IGF-I receptor signaling in a prostatic cancer cell line with a PTEN mutation. Oncogene. 2000; 19 2687-2694
34 Tseng Y H, Ueki K, Kriauciunas K M, Kahn C R. Differential roles of insulin receptor substrates in the anti-apoptotic function of insulin-like growth factor-I and insulin. J Biol Chem. 2002; 277 31 601-31 611
35 Cai D, Dhe-Paganon S, Melendez P A, Lee J, Shoelson S E. Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem. 2003; 278 25 323-25 330
36 Gu H, Neel B G. The ,Gab’ in signal transduction. Trends Cell Biol. 2003; 13 122-130
37 Wick K R. et al . Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. J Biol Chem. 2003; 278 8460-8467
38 Vecchione A, Marchese A, Henry P, Rotin D, Morrione A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol. 2003; 23 3363-3372
39 Kiely P A, Sant A, O’Connor R. RACK1 is an IGF-1 Receptor interacting protein that can regulate IGF-1- mediated Akt activation and protection from cell death. J Biol Chem. 2002; 277 22581-22589
40 Hermanto U, Zong C S, Li W, Wang L H. RACK1, an insulin-like growth factor I (IGF-I) receptor-interacting protein, modulates IGF-I-dependent integrin signaling and promotes cell spreading and contact with extracellular matrix. Mol Cell Biol. 2002; 22 2345-2365
41 Mochly-Rosen D, Smith B L, Chen C H, Disatnik M H, Ron D. Interaction of protein kinase C with RACK1, a receptor for activated C-kinase: a role in beta protein kinase C mediated signal transduction. Biochem Soc Trans. 1995; 23 596-600
42 Berns H, Humar R, Hengerer B, Kiefer F N, Battegay E J. RACK1 is up-regulated in angiogenesis and human carcinomas. Faseb J. 2000; 14 2549-2558
43 McCahill A, Warwicker J, Bolger G B, Houslay M D, Yarwood S J. The RACK1 scaffold protein: a dynamic cog in cell response mechanisms. Mol Pharmacol. 2002; 62 1261-1273
44 Chang B Y, Conroy K B, Machleder E M, Cartwright C A. RACK1, a receptor for activated C kinase and a homolog of the beta subunit of G proteins, inhibits activity of src tyrosine kinases and growth of NIH 3T3 cells. Mol Cell Biol. 1998; 18 3245-3256
45 Valentinis B, Morrione A, Taylor S J, Baserga R. Insulin-like growth factor I receptor signaling in transformation by src oncogenes. Mol Cell Biol. 1997; 17 3744-3754
46 Frame M C, Fincham V J, Carragher N O, Wyke J A. v-Src’s hold over actin and cell adhesions. Nat Rev Mol Cell Biol. 2002; 3 233-245
47 O’Connor R. et al . Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol. 1997; 17 427-435
48 Stahl J M. et al . Loss of PTEN promotes tumor development in malignant melanoma. Cancer Res. 2003; 63 2881-2890
49 Haj F G, Verveer P J, Squire A, Neel B G, Bastiaens P I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science. 2002; 295 1708-1711
50 Buckley D A, Cheng A, Kiely P A, Tremblay M L, O’Connor R. Regulation of insulin-like growth factor type I (IGF-I) receptor kinase activity by protein tyrosine phosphatase 1B (PTP-1B) and enhanced IGF-I- mediated suppression of apoptosis and motility in PTP-1B-deficient fibroblasts. Mol Cell Biol. 2002; 22 1998-2010
51 Haj F G, Markova B, Klaman L D, Bohmer F D, Neel B G. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J Biol Chem. 2003; 278 739-744
52 Dadke S, Chernoff J. Protein-tyrosine phosphatase 1B mediates the effects of insulin on the actin cytoskeleton in immortalized fibroblasts. J Biol Chem. 2003; 278 40607-40611
53 Tonks N K. PTP1B: from the sidelines to the front lines!. FEBS Lett. 2003; 546 140-148
54 Maile L A, Clemmons D R. The alphaVbeta3 integrin regulates insulin-like growth factor I (IGF-I) receptor phosphorylation by altering the rate of recruitment of the Src- homology 2-containing phospho tyro sine phosphatase-2 to the activated IGF-I receptor. Endocrinology. 2002; 143 4259-4264
55 Araki T, Nawa H, Neel B G. Tyrosyl phosphorylation of Shp2 is required for normal Erk activation in response to some, but not all growth factors. J Biol Chem. 2003; 278 41677-41684
56 Steck P A. et al . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997; 15 356-362
57 Li J. et al . PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997; 275 1943-1947
58 Stambolic V. et al . Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998; 95 29-39
59 Simpson L. et al . PTEN expression causes feedback upregulation of insulin receptor substrate 2. Mol Cell Biol. 2001; 21 3947-3958
60 Sasaoka T, Kikuchi K, Wada T, Sato A, Hori H, Murakami S, Fukui K, Ishihara H, Aota R, Kimura I, Kobayashi M. Dual role of SRC homology domain 2-containing inositol phosphatase 2 in the regulation of platelet-derived growth factor and insulin-like growth factor I signaling in rat vascular smooth muscle cells. Endocrinology. 2003; 144 4204-4214
61 Ivaska J. et al . Integrin alpha 2 beta 1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta. Mol Cell Biol. 2002; 22 1352-1359
62 Ugi S, Sharma P M, Ricketts W, Imamura T, Olefsky J M. Phosphatidylinositol 3-kinase is required for insulin-stimulated tyrosine phosphorylation of Shc in 3T3-L1 adipocytes. J Biol Chem. 2002; 277 18 592-18 597

R. O'Connor

Cell Biology Laboratory · Department of Biochemistry · BioSciences Institute · National University of Ireland

Cork · Ireland

Phone: +353 (21) 490 13 12

Fax: + 353 (21) 490 13 82

Email: r.oconnor@ucc.ie