Beruflich Dokumente
Kultur Dokumente
REVIEW ARTICLE
Archives of Physiology and Biochemistry Downloaded from informahealthcare.com by University of Alberta on 06/06/13
For personal use only.
Abstract
Insulin and the insulin-like growth factors (IGF-I, IGF-II) are pleiotropic hormones that have multiple roles in regulating
vital metabolic and developmental processes. Although most early data suggested that insulin is mainly involved in metabolic
activities (e.g. control of sugar levels) and IGF-I/II control growth and differentiation events (e.g. bone elongation, cell
division), today, it is clear that there is cross-talk between the various ligands and receptors of the IGF family. As a result of
these complex interactions, the spectrum of activities that were classically assigned to insulin or IGF-I/II has greatly
expanded, and the signalling events mediated by the insulin and IGF receptors is the subject of intensive research. This
review provides a comparative analysis of the structures, receptors, and signalling pathways of insulin and IGF-I.
Key words: Insulin, insulin-like growth factor (IGF), insulin receptor, signalling.
Introduction
Accurate control of the processes of cellular growth
and differentiation is a fundamental requisite that
ensures that the organism will properly develop and
function. The wealth of information that has
accumulated over the past several years on the
insulin and insulin-like growth factors (IGFs) provides a unique paradigm of a composite family of
hormones, cell-surface receptors, extra-cellular binding proteins (IGFBPs), and additional accessory
components that, in a remarkably orchestrated
manner, regulate multiple biological processes
(LeRoith et al., 2001; Rosenfeld, 2005; Werner &
LeRoith, 2000). Most clinical and experimental data
collected since the discovery of the IGFs in the mid1950s suggested a division of labour among
insulin, IGF ligands, and receptors. This compartmentalization of functions provided the foundation
for the classical dogma that prevailed for many years
in the field, which attributed a primarily metabolic
role to the insulin receptor (IR) pathway and a
mitogenic/proliferative role to the IGF-I receptor
(IGF-IR) pathway. However, new information generated in recent years has clearly demonstrated that
many of these old concepts, although correct
regarding their basic assumptions, are essentially
Archives of Physiology and Biochemistry Downloaded from informahealthcare.com by University of Alberta on 06/06/13
For personal use only.
18
H. Werner et al.
19
Archives of Physiology and Biochemistry Downloaded from informahealthcare.com by University of Alberta on 06/06/13
For personal use only.
Precursor size
Signal peptide size
Predicted Mr of
precursor
Predicted Mr of
a-subunit
Predicted Mr of
b-subunit
Location of Arg-LysArg-Arg sequence
(cleavage site)
a-subunit size
b-subunit size
Transmembrane
domain
Insulin receptor
IGF-I receptor
82,400
80,423
69,700
70,866
At position 720
At position 707
Homology (%)
84
64 67
48
27
Archives of Physiology and Biochemistry Downloaded from informahealthcare.com by University of Alberta on 06/06/13
For personal use only.
20
H. Werner et al.
In addition, and in agreement with its well-documented cell survival role, the initial proliferative
switch in oncogene-induced transformation was
correlated with focal activation of IGF-II (Christofori
et al., 1994). Transfection with an anti-sense
oligonucleotide to the IGF-II mRNA interfered with
tumour cell proliferation in vitro, and transgenic mice
homozygous for a disruption of the IGF-II gene
developed tumours with reduced malignancy. Combined, these results suggest that, in addition to the
oncoprotein, IGF-II signalling is necessary to elicit
hyperproliferation.
Finally, it was demonstrated that IGF-IR protects
cells from apoptotic death in multiple cultured cells
as well as in vivo (Resnicoff et al., 1995; Sell et al.,
1995). A highly significant positive correlation was
found between cell survival and the number of cellsurface IGF-IRs. Furthermore, elevated levels of
cell-surface IGF-IR allowed cells to switch from a
nonmitogenic to a mitogenic mode, whereas
above a certain threshold value, cells acquired the
ability to grow in soft agar (Rubini et al., 1997).
As mentioned above, ligand binding to the extracellular domains of IR or IGF-IR leads to autophosphorylation of the receptors on tyrosine residues.
These phosphotyrosines are docking sites for SH2
domain-containing substrates, including the insulin
receptor substrate (IRS)1-4, Shc, and others. These
substrates, in turn, undergo phosphorylation, leading
to activation of the PI3K-Akt/PKB and Ras-RafMAPK pathways. Interestingly, the vast majority of
the components of these pathways are shared by both
receptors, raising the question how IR and IGF-IR
succeed in engaging in basically different biological
activities (Dupont & LeRoith, 2001; LeRoith et al.,
1995). A number of potential mechanisms were
postulated to explain this paradox, including a
different tissue distribution of IR and IGF-IR
(Werner et al., 1991), different internalization kinetics and sub-cellular distribution of the hormonereceptor complex (Zapf et al., 1994), as well as
different hormone-receptor affinities (Mastick et al.,
1998) (Table III). In addition, various substrates and
21
Archives of Physiology and Biochemistry Downloaded from informahealthcare.com by University of Alberta on 06/06/13
For personal use only.
References
Abbott AM, Bueno R, Pedrini MT, Murray JM, Smith RJ. 1992.
Insulin-like growth factor I receptor gene structure. J Biol
Chem 267:10759 63.
Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P,
Asico LD, Jose PA, Taylor SI, Westphal H. 1996. Early
neonatal death in mice homozygous for a null allele of the
insulin receptor gene. Nature Genetics 12:106 9.
Alarcon C, Morales AV, Pimentel B, Serna J, de Pablo F. 1998.
(Pro)insulin and insulin-like growth factor I complementary
expression and roles in early development. Comp Biochem
Physiol B Biochem Mol Biol 121:13 17.
Baker J, Liu J-P, Robertson EJ, Efstratiadis A. 1993. Role of
insulin-like growth factors in embryonic and postnatal growth.
Cell 75:73 82.
Baxter RC. 2000. Insulin-like growth factor-binding proteins:
interactions with IGFs and intrinsic bioactivities. Am J Physiol
278:967 76.
Bayne ML, Applebaum J, Underwood D, Chicchi GG, Green BG,
Hayes NS, Cascieri MA. 1989. The C region of the human
insulin-like growth factor (IGF) I is required for high affinity
binding to the type 1 IGF receptor. J Biol Chem 264:11004
11.
Bendall SC, Stewart MH, Menendez P, George D, Vijayaragavan
K, Werbowetski-Ogilvie T, Ramos-Mejia V, Rouleau A, Yang
J, Bosse M, et al. 2007. IGF and FGF cooperatively establish
the regulatory stem cell niche of pluripotent human cells in
vitro. Nature 448:1015 23.
Bentov I, Werner H. 2004. IGF, IGF receptor and overgrowth
syndromes. Pediatr Endocrinol Rev 1:352 60.
Bentov I, Werner H. 2006. Insulin-like growth factor-I. In: Kastin
A, editor. Handbook of Biologically Active Peptides. San
Diego: Elsevier Press; pp 1385 92.
Christofori G, Naik P, Hanahan D. 1994. A second signal supplied
by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369:414 18.
DeChiara TM, Efstratiadis A, Robertson EJ. 1990. A growthdeficiency phenotype in heterozygous mice carrying an insulinlike growth factor II gene disrupted by targeting. Nature
345:78 80.
Denley A, Brierley GV, Carroll JM, Lindenberg A, Booker GW,
Cosgrove L, Wallace JC, Forbes BE, Roberts Jr CT. 2006.
Differential activation of insulin receptor isoforms by insulinlike growth factors is determined by the C domain. Endocrinology 147:1029 36.
Dupont J, LeRoith D. 2001. Insulin and insulin-like growth factorI receptors: similarities and differences in signal transduction.
Hormone Research 55(Suppl. 2):22 6.
Ebina Y, Ellis L, Jarnagin K, Edery M, Graf L, Clauser E, Qu J,
Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ. 1985.
The human insulin receptor cDNA: the structural basis
for hormone-activated transmembrane signalling. Cell 40:
747 58.
Archives of Physiology and Biochemistry Downloaded from informahealthcare.com by University of Alberta on 06/06/13
For personal use only.
22
H. Werner et al.
Florini JR, Ewton DZ. 1990. Highly specific inhibition of IGF-Istimulated differentiation by an antisense oligodeoxyribonucleotide to myogenin mRNA. No effects on other actions of
IGF-I. J Biol Chem 265:13435 7.
Frasca F, Pandini G, Scalia R, Sciacca L, Mineo R, Constantino
A, Goldfine ID, Belfiore A, Vigneri R. 1999. Insulin receptor
isoform A, a newly recognized, high-affinity insulin-like growth
factor II receptor in fetal and cancer cells. Mol Cell Biol
19:3278 88.
Grill CJ, Cohick WS. 2000. Insulin-like growth factor binding
protein-3 mediates IGF-I action in a bovine mammary
epithelial cell line independent of an IGF interaction. J Cell
Physiol 183:273 83.
Guler HP, Zapf J, Froesch ER. 1987. Short-term metabolic effects
of recombinant human insulin-like growth factor I in healthy
adults. New England J Med 317:137 40.
Holly J, Perks C. 2006. The role of insulin-like growth factor
binding proteins. Neuroendocrinology 83:154 60.
Jacobs S, Kull FC Jr, Cuatrecasas P. 1983. Monensin blocks the
maturation of receptors for insulin and somatomedin C:
identification of receptor precursors. Proc Natl Acad Sci
USA 80:1228 32.
Kjeldsen T, Andersen AS, Wiberg FC, Rasmussen JS, Schaffer L,
Balschmidt P, Moller KB, Moller NPH. 1991. The ligand
specificities of the insulin receptor and the insulin-like growth
factor I receptor reside in different regions of a common
binding site. Proc Natl Acad Sci USA 88:4404 8.
Klammt J, Garten A, Barnikol-Oettler A, Beck-Sickinger AG,
Kiess W. 2005. Comparative analysis of the signalling
capabilities of the insulin receptor-related receptor. Biochem
Biophys Res Comm 327:557 64.
Laviola L, Giorgino F, Chow JC, Baquero JA, Hansen H, Ooi J,
Zhu J, Riedel H, Smith RJ. 1997. The adapter protein Grb10
associates preferentially with the insulin receptor as compared
with the IGF-I receptor in mouse fibroblasts. J Biol Chem
99:830 7.
Leboulleux S, Gaston V, Boulle N, Le Bouc Y, Gicquel C. 2001.
Loss of heterozygosity at the mannose-6-phosphate/insulin-like
growth factor 2 receptor locus: a frequent but late event in
adrenocortical tumorigenesis. Eur J Endocrinol 144:163 8.
LeRoith D, Bondy C, Yakar S, Liu J-L, Butler A. 2001. The
Somatomedin hypothesis: 2001. Endocrine Rev 22:53 74.
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. 1995.
Molecular and cellular aspects of the insulin-like growth factor
I receptor. Endocrine Rev 16:143 63.
Liu J-P, Baker J, Perkins AS, Robertson EJ, Estratiadis A. 1993.
Mice carrying null mutations of the genes encoding insulin-like
growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell
75:59 72.
Lu K, Campisi J. 1992. Ras proteins are essential and selective for
the action of insulin-like growth factor 1 late in the G1 phase of
the cell cycle in BALB/c murine fibroblasts. Proc Natl Acad Sci
USA 89:3889 93.
Macaulay VM. 1992. Insulin-like growth factors and cancer. Br J
Cancer 65:311 20.
Mastick CC, Brady MJ, Printen JA, Ribon V, Saltiel AR. 1998.
Spatial determinants of specificity in insulin action. Mol Cell
Biochem 182:65 71.
Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth
RA, Rutter WJ. 1987. Insulin-like growth factor II receptor as a
multifunctional binding protein. Nature 329:301 7.
Morrione A, Valentinis B, Xu S, Yumet G, Louvi A, Efstratiadis
A, Baserga R. 1997. Insulin-like growth factor II stimulates cell
proliferation through the insulin receptor. Proc Natl Acad Sci
USA 94:3777 82.
Moschos SJ, Mantzoros CS. 2002. The role of the IGF system in
cancer: from basic to clinical studies and clinical applications.
Oncology 63:317 32.
Najjar SM, Blakesley VA, Li Calzi S, Kato H, LeRoith D, Choice
CV. 1997. Differential phosphorylation of pp120 by insulin and
insulin-like growth factor I receptors: role for the C-terminal
domain of the beta-subunit. Biochemistry 36:6827 34.