REVIEW ARTICLE

Similarities and differences between insulin and IGF-I: Structures,receptors, and signalling pathways

HAIM WERNER, DORON WEINSTEIN, & ITAY BENTOV

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv

69978, Israel

AbstractInsulin and the insulin-like growth factors (IGF-I, IGF-II) are pleiotropic hormones that have multiple roles in regulatingvital metabolic and developmental processes. Although most early data suggested that insulin is mainly involved in metabolicactivities (e.g. control of sugar levels) and IGF-I/II control growth and differentiation events (e.g. bone elongation, celldivision), today, it is clear that there is cross-talk between the various ligands and receptors of the IGF family. As a result ofthese complex interactions, the spectrum of activities that were classically assigned to insulin or IGF-I/II has greatlyexpanded, and the signalling events mediated by the insulin and IGF receptors is the subject of intensive research. Thisreview 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) pro-

vides a unique paradigm of a composite family of

hormones, cell-surface receptors, extra-cellular bind-

ing 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 mid-

1950s suggested a ‘‘division of labour’’ among

insulin, IGF ligands, and receptors. This compart-

mentalization 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 gen-

erated in recent years has clearly demonstrated that

many of these ‘‘old’’ concepts, although correct

regarding their basic assumptions, are essentially

oversimplifications of much more complex situations

(Bentov & Werner, 2004; Yakar et al., 2005). As a

result, there is an urgent need to revise deep-rooted

notions and ideas in order to be able to coherently

and rationally describe the metabolic and growth

processes associated with the insulin/IGF family. The

purpose of this review is to analyse in a comparative

manner the physiological and pathological roles of

some of the members of the insulin/IGF family, in

particular, ligands and receptors.

The insulin-like ligands

The insulin-like ligands comprise at least nine

different genes: two non-allelic insulin genes (in

rodents), igf-1, igf-2, relaxin, and four insulin-like

peptides (ins-3 to -6) (Nakae et al., 2001). The

physiological roles of the non-classical ligands are,

obviously, less well characterized than those of

insulin, IGF-I, and IGF-II. The biological spectrum

of ligand activities is dictated by a number of

parameters, including their affinities for the specific

receptors, their sites of synthesis [‘‘Are they pro-

duced by one single organ, e.g. insulin, or by

multiple tissues, e.g. the IGFs?’’], their affinities for

the IGFBPs [‘‘Do they circulate bound to carrier

proteins, e.g. the IGFs, or unligated, e.g. insulin?’’]

Correspondence: Haim Werner. Tel: 972-3-640-8542. Fax: 972-3-640-6087. E-mail: hwerner@post.tau.ac.il

Received for publication 6 November 2007. Accepted 8 January 2008.

Archives of Physiology and Biochemistry, February 2008; 114(1): 17 – 22

ISSN 1381-3455 print/ISSN 1744-4160 online ª 2008 Informa UK Ltd.

DOI: 10.1080/13813450801900694

Arc

hive

s of

Phy

siol

ogy

and

Bio

chem

istr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Alb

erta

on

06/0

6/13

For

pers

onal

use

onl

y.

and, finally, the signalling events elicited following

activation of the receptor.

The original ‘‘somatomedin hypothesis’’, formu-

lated in the late 1950s, following the identification of

‘‘somatomedin’’ by Salmon and Daughaday (1957),

proposed that growth hormone (GH) governs so-

matic growth by stimulating hepatic production of

IGF-I. This hypothesis was modified in the 1980s to

incorporate the discovery that IGF-I was, in fact,

produced by most body tissues (in addition to the

liver) and, consequently, may exert both endocrine

and autocrine/paracrine types of activities. This

revised version of the hypothesis also embraced the

notion that IGF actions were modulated by the

IGFBPs, which control the fraction of ‘‘free’’,

bioavailable IGF-I. In 1999 the publication of the

phenotype of animals with a liver-specific IGF-I gene

disruption, by Yakar et al. (LeRoith et al., 2001;

Yakar et al., 1999), led to a further revision of the

somatomedin hypothesis. Specifically, the observa-

tion that a drastic reduction in serum IGF-I levels

did not result in a growth deficit indicated that locally

produced IGF-I, rather than hepatic IGF-I, is the

critical determinant of growth and development.

Alternatively, the contemporary interpretation of the

somatomedin hypothesis is compatible with the

possibility that levels of free IGF-I are sufficient to

maintain their growth-promoting activities despite a

large reduction in total IGF-I levels.

The structural and functional similarities between

insulin and IGF-I suggest that both molecules are

derived from a common ancestral precursor that

probably participated in food intake and regulation of

cellular growth (Alarcon et al., 1998; Rinderknecht &

Humbel, 1978). A divergence of functions most

likely occurred before the appearance of the first

vertebrates, with insulin mostly active in the regula-

tion of metabolism and IGF-I in growth processes.

However, in view of their common evolutionary

origins and semi-conserved architecture, there is a

certain degree of cross-talk between insulin, IGF-I,

and their receptors (Werner et al., 1991). Accord-

ingly, insulin exhibits a number of IGF-I-like

activities, including growth stimulation, whereas

IGF-I, on the other hand, exerts several metabolic

effects. In addition, the fact that IGF-I, but not

insulin, is carried in the circulation and extracellular

fluid by IGFBPs further contributes to the divergent

actions of the ligands.

An additional parameter that contributes to the

divergent biological activities of the insulin-like

peptides is the developmental stage. Ontogenetic

analyses in rodents have revealed low IGF-I levels

and high IGF-II levels during the prenatal period,

whereas postnatal stages are characterized by an

increase in circulating IGF-I and the disappearance

of IGF-II. These observations might have led to an

erroneous generalized interpretation of the roles of

IGF-II and IGF-I as foetal and pubertal growth

factors, respectively. In humans, however, this

expression pattern does not exist and both ligands

are produced from the prenatal to the postnatal

periods. In fact, in normal healthy adults circulating

IGF-II levels are higher than IGF-I levels (Bentov &

Werner, 2004).

The insulin-like receptors

The classical insulin-like receptors comprise the IR,

IGF-IR, and IGF-IIR family (Ebina et al., 1985;

Ullrich et al., 1985; Ullrich et al., 1986). An

additional receptor molecule is the insulin receptor-

related receptor (IRR), although the specific ligand

involved in IRR binding and activation has not yet

been identified (Klammt et al., 2005; Shier & Watt,

1989). IR, IGF-IR, and IRR are members of the

ligand-activated receptor kinase superfamily. Upon

ligand activation, the receptors undergo a conforma-

tional change that leads to ATP binding and

autophosphorylation of the tyrosine kinase domain.

This event, in turn, enhances the kinase activity of

the receptors and confers upon them the ability to

phosphorylate a series of cytoplasmic substrates,

collectively referred to as ‘‘downstream signal trans-

duction mediators’’. Most available evidence is

consistent with the view that both IGF-I and IGF-

II activate the ubiquitously expressed IGF-IR with

relatively similar affinities (see below).

The IGF-IR, like the IR, is synthesized as a single

polypeptide chain that is processed to yield a

glycopeptide of Mr 180 kDa (Jacobs et al., 1983;

Werner et al., 1991). Precursor chains include at

their N-terminal domain a signal peptide rich in

polar residues, which is involved in the transfer of

the nascent protein into the endoplasmic reticulum.

Partially processed proreceptors form disulfide-

linked dimers that are subsequently glycosylated

and proteolytically cleaved at a basic tetrapeptide

sequence (Arg-Lys-Arg-Arg) to yield mature a and

b subunits. The mature heterotetramers have a b –

a – a – b conformation. Structurally, the a subunits

of the mature receptors reside entirely extracellu-

larly and include a cysteine-rich region and several

potential N-linked glycosylation sites (Asn-X-Ser/

Thr motifs). The cysteine-rich domain of the IGF-

IR is important for high-affinity IGF-I binding,

unlike the IR in which regions N- and C-terminal to

this domain are critical for insulin binding (Kjeldsen

et al., 1991). Interestingly, the b subunit features a

unique hydrophobic sequence that constitutes the

transmembrane domain. The juxtamembrane do-

main contains an Asn-Pro-X-Tyr motif that is

important for receptor internalization and biological

functioning of both IR and IGF-IR. Finally, the

cytoplasmic portions of the b subunits contain a

tyrosine kinase enzymatic domain. Inside this

catalytic region, there is a glycine-rich conserved

element (Gly-X-Gly-X-X-Gly) that participates in

the transfer of the phosphate moiety of ATP to

specific substrates.

18 H. Werner et al.

Arc

hive

s of

Phy

siol

ogy

and

Bio

chem

istr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Alb

erta

on

06/0

6/13

For

pers

onal

use

onl

y.

Molecular cloning of the IGF-IIR revealed that a

single cell-surface receptor is able to bind both

mannose 6-phosphate (M6P)-containing moieties

and IGF-II molecules (Morgan et al., 1987). The

IGF-II/M6P-R is a monomeric receptor with a large

extracellular domain composed of 15 repeat se-

quences and a small region homologous to the

collagen-binding domain of fibronectin. The IGF-

II/M6P-R targets IGF-II for lysosomal degradation

and thus reduces the bioavailability of circulating

IGF-II. Diminished levels of IGF-II lead to de-

pressed activation of the IGF-IR. In accordance with

these findings, the IGF-II/M6P-R has been defined

as a tumour suppressor gene product (Leboulleux

et al., 2001). Consistent with this definition,

several neoplasms feature a mutated or deleted

IGF-II/M6P-R.

Genomic and structural comparisons between

IR and IGF-IR

There is a striking similarity in the genomic

organization of the IR and IGF-IR (Table I) (Abbott

et al., 1992; Seino et al., 1989). Twelve exons (out of

21) of the IGF-IR gene are identical in size with the

homologous exons of the IR. Furthermore, with the

exception of the first and last exons, differences in

size between the remaining homologous exons do not

exceed 15 nucleotides. As expected from their

conserved gene arrangements, the primary structures

of the IR and IGF-IR proteins also share a high

degree of similarity. For example, the length of the IR

precursor is 1370 amino acids (including a 27-amino

acid signal peptide), compared with 1367 amino

acids (including a 30-amino acid leader peptide) for

the IGF-IR. The highest similarity (84%) between

both molecules is found in the tyrosine kinase

domain of the b subunit (Table II). Relatively high

resemblance (64% – 67%) is also found between the

extracellular a subunit regions flanking the cysteine-

rich domains. The cysteine-rich domains themselves

exhibit 48% homology, despite conservation in the

IGF-IR of 24 out of 26 cysteines that are present in

the IR. In addition, 15 out of 16 putative N-linked

glycosylation sites (Asn-X-Thr/Ser) in the extracel-

lular region of the IGF-IR are located at almost

identical positions in the IR. The lowest amino acid

identity (27%) is found in exon 14 of the IGF-IR,

which contains sequences encoding the membrane-

spanning domain. Taken together, the impressive

similarity in overall structure between these two

genes is consistent with the notion that both receptor

genes share a common evolutionary origin.

However, despite a remarkable similarity between

the receptors, each ligand exhibits high-affinity

binding to its cognate receptor (Bayne et al., 1989;

Rechler et al., 1980; Tollefsen & Thompson, 1988).

Scatchard analysis of IGF-I and IGF-II binding to

the IGF-IR generates a linear plot, suggesting a

single class of receptors with an affinity of *10710

M. Insulin binds to the IGF-IR with lower affinity

(1078 M). On the other hand, IR yields curvilinear

plots that typically suggest the presence of high

(*10710 M) and low affinity binding sites. IGF-II

binds the IR with an affinity 10- to 50-fold lower than

that of insulin, and IGF-I with an affinity 100- to

500-fold lower. Interestingly, IGF-II can also signal

via IR-A, a particular isoform of the IR that is

generated by alternative splicing of the IR gene

(Denley et al., 2006; Frasca et al., 1999; Morrione

et al., 1997). In addition to their divergent affinities,

differences between IR and IGF-IR activities were

postulated to result from the different sets of down-

stream targets that are activated by each receptor (see

below). Furthermore, the pattern of expression of

each receptor may explain the preferential effects of

each ligand in particular organs and at specified

developmental stages. Thus, high levels of IR are

found in liver and adipose tissue, whereas IGF-IRs

are essentially absent in liver and present at low levels

in adipose tissue (Dupont & LeRoith, 2001).

Insulin-like growth factor binding proteins

The substantial majority of IGF peptides in the

circulation are not found in a free form, but rather in

a ternary complex that includes, in addition to the

IGF ligand, a liver-derived glycoprotein (the acid-

labile subunit, ALS) and a high-affinity binding

protein, the IGF-binding protein 3 (IGFBP3). Six

IGFBPs (IGFBP1-6) and a number of IGFBP-

related proteins have been characterized to date

Table I. Structural comparison of insulin and IGF-I receptors.

Insulin receptor IGF-I receptor

Precursor size 1370 amino acids 1367 amino acids

Signal peptide size 27 amino acids 30 amino acids

Predicted Mr of

precursor

152,000 151,869

Predicted Mr of

a-subunit

82,400 80,423

Predicted Mr of

b-subunit

69,700 70,866

Location of Arg-Lys-

Arg-Arg sequence

(cleavage site)

At position 720 At position 707

a-subunit size 719 amino acids 706 amino acids

b-subunit size 620 amino acids 627 amino acids

Transmembrane

domain

Residues 915

(or 918) – 940

Residues 906 – 929

Table II. Homology between insulin and IGF-I receptors.

Receptor domain Homology (%)

b-subunit tyrosine kinase domain 84

a-subunit regions flanking the

cysteine-rich domain

64 – 67

a-subunit cysteine-rich domain 48

b-subunit transmembrane domain 27

Similarities and differences between insulin and IGF-I 19

Arc

hive

s of

Phy

siol

ogy

and

Bio

chem

istr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Alb

erta

on

06/0

6/13

For

pers

onal

use

onl

y.

(Holly & Perks, 2006). IGFBP3, the predominant

IGFBP in serum, is the largest and, therefore, the

only one that cannot traverse the capillary mem-

brane. The ternary complex among IGF-I, IGFBP3,

and ALS modulates IGF-I action by protecting the

growth factor from proteolysis and prolonging its half

live in the circulation (Baxter, 2000). In addition,

some IGFBPs exert their biological effects in an IGF-

independent manner (Grill & Cohick, 2000). In

general, the IGFBPs inhibit IGFs’ metabolic and

proliferative actions, although some IGFBPs may

display IGF-potentiating effects as well. IGFBP3, in

particular, is recognized as an inhibitor of prolifera-

tion, driving the cell to apoptosis. Several potential

mechanisms were postulated to explain IGFBP-3

inhibition of IGF action, including sequestration of

IGF-I from the receptor and binding competition

with the IGF-IR. As alluded to above, the fact that

the biological actions of insulin are not affected by

circulating or extracellular IGF-BPs is one of the key

aspects that demarcate the spectrum of actions of

insulin compared with those of IGF-I.

Biological actions of IGF-I and IGF-II

At the cellular level, IGF-I stimulates a mitogenic

response and inhibits cell death in a wide variety of

cell types, including primary cultures and cancer cell

lines (Macaulay, 1992). Quiescent cells in G0 can be

induced to enter G1 by competence factors (e.g.

PDGF, bFGF). Once the cell enters into G1, sub-

physiological doses of IGF-I will allow it to evade

arrest in G1 and to progress through the cell cycle

(Lu & Campisi, 1992). Thus, IGF-I functions as a

progression factor (Moschos & Mantzoros, 2002).

IGF-I can also induce differentiation and this activity

can be blocked by specific anti-sense oligonucleo-

tides (Florini & Ewton, 1990). IGF-I exhibits a

variety of cellular functions, including regulation of

hormone synthesis and secretion, chemoattractant

migration, immune cell recognition, and neuromo-

dulation (Bentov & Werner, 2006). Metabolic effects

of IGF-I include elevation of glucose uptake and

hypoglycemia, without lowering free fatty acid levels.

In addition, IGF-I was shown to improve renal

function by increasing renal blood flow and the

glomerular filtration rate (Guler et al., 1987).

IGF-II is a bifunctional ligand that can stimulate

both IR and IGF-IR signalling, although with

different potencies (Nakae et al., 2001). Recent

studies have identified IGF-II as a key regulator of

pluripotent human embryonic stem cells (Bendall

et al., 2007). Specifically, IGF-II, but not IGF-I, was

shown to play a direct, supportive role in embryonic

stem cells. IGF-II and IGF-IR transcripts were

shown to be expressed in both human and mouse

blastocysts, and IGF-IR-mediated signalling was

required for survival of the mouse inner cell mass.

These studies demonstrate a direct role of the IGF-

II/IGF-IR axis on embryonic stem cell physiology.

In addition, and in agreement with its well-docu-

mented 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. Com-

bined, 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 cell-

surface 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).

Signalling pathways: similarities and

differences

As mentioned above, ligand binding to the extra-

cellular domains of IR or IGF-IR leads to autopho-

sphorylation 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-Raf-

MAPK 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 ki-

netics and sub-cellular distribution of the hormone-

receptor complex (Zapf et al., 1994), as well as

different hormone-receptor affinities (Mastick et al.,

1998) (Table III). In addition, various substrates and

Table III. Potential mechanisms responsible for IR and IGF-IR

differential activation.

Differences in cellular expression of IR and IGF-IR

(predominant IR expression in liver and adipose tissue).

Differences in internalization and subcellular distribution of the

ligand-receptor complex following receptor activation on the

cell surface.

Differences in ligand-receptor affinities.

Differences in substrate specificities and signalling potentials.

Preferential activation of specific substrates by insulin or IGF-I.

Preferential binding of IGF-BPs to IGFs but not to insulin.

20 H. Werner et al.

Arc

hive

s of

Phy

siol

ogy

and

Bio

chem

istr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Alb

erta

on

06/0

6/13

For

pers

onal

use

onl

y.

signalling mediators that are preferentially activated

by insulin or IGF-I have been identified. For

example, the adapter protein Grb10 associates

mainly with IR but not with IGF-IR (Laviola et al.,

1997). Similarly, the IR, but not the IGF-IR,

interacts with pp120 (Najjar et al., 1997). Differential

activation of these and other substrates may partially

explain the receptor specificity.

Lessons from animal models

The essential role played by the IGF system in

growth and development was demonstrated by the

growth deficits observed in mice in which various

components of the IGF system were disrupted by

homologous recombination (Baker et al., 1993).

Targeted disruption of the IGF-II gene resulted in

mice weighing 60% of their normal littermates at

the time of birth (DeChiara et al., 1990). However,

the reduction in growth rate was restricted to the

embryonic period and the animals developed into

essentially normal and proportionate fertile dwarfs.

The phenotype of null mutants for the IGF-I gene is

more complex and depends on the genetic back-

ground of the animals. Thus, some of these mice

died shortly after birth, whereas others survived and

reached adulthood (Liu et al., 1993). Surviving IGF-

I-null mice manifested, among other abnormalities, a

delay in the ossification process, underdeveloped

muscles and lungs, and infertility. Mice heterozygous

for a disrupted IGF-I gene exhibited no major

growth retardation (10 – 20% less than wild-type

littermates), whereas null homozygotes weighed

*40% less than wild types (Powell-Braxton et al.,

1993). Furthermore, null homozygotes had very high

perinatal mortality rates and a number of phenotypic

aberrations.

Homozygous IGF-IR knockout mice exhibited the

most severe developmental retardation. These ani-

mals, which invariably died at birth, weighed only

45% of normal controls and displayed hypoplasia,

abnormal skin formation, delayed bone develop-

ment, and anomalous central nervous system mor-

phology (Liu et al., 1993). Ablation of the IR gene

resulted in mice displaying no major developmental

delay at the time of birth (*90% of normal

littermates). These animals, however, died during

the first several days of postnatal life as a result of

diabetic ketoacidosis (Accili et al., 1996).

Summary

Over the past two decades new information has

accumulated about the physiological and pathologi-

cal functions of the insulin/IGF system. These novel

data were generated using genetic tools (transgenic

and knockout animal models) as well as classical

biochemical, molecular, and endocrinological meth-

ods. In addition, valuable information was acquired

from the clinics. As outlined in this review, much

essential information remains to be elucidated,

including the factors responsible for the specific

activities of the insulin and IGF signalling pathways,

and the distinct roles each pathway plays in cancer.

Understanding the basis of these events at the

molecular, cellular and organism levels will be of

significant basic and clinical relevance.

Acknowledgement

Work in the laboratory of H.W. is supported in part

by a grant from the Insulin Dependent Diabetes

Trust, United Kingdom.

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 tumor-

igenesis. Nature 369:414 – 18.

DeChiara TM, Efstratiadis A, Robertson EJ. 1990. A growth-

deficiency phenotype in heterozygous mice carrying an insulin-

like 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 insulin-

like growth factors is determined by the C domain. Endocri-

nology 147:1029 – 36.

Dupont J, LeRoith D. 2001. Insulin and insulin-like growth factor-

I 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.

Similarities and differences between insulin and IGF-I 21

Arc

hive

s of

Phy

siol

ogy

and

Bio

chem

istr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Alb

erta

on

06/0

6/13

For

pers

onal

use

onl

y.

Florini JR, Ewton DZ. 1990. Highly specific inhibition of IGF-I-

stimulated differentiation by an antisense oligodeoxyribonu-

cleotide 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.

Nakae J, Kido Y, Accili D. 2001. Distinct and overlapping

functions of insulin and IGF-I receptors. Endocrine Rev

22:818 – 35.

Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-

Meek S, Dalton D, Gillett N, Stewart TA. 1993. IGF-I is

required for normal embryonic growth in mice. Genes and

Development 7:2609 – 17.

Rechler M, Zapf J, Nissley S, Froesch E, Moses A, Podskalny J,

Schilling E, Humbel R. 1980. Interactions of insulin-like

growth factors I and II and multiplication-stimulating activity

with receptors and serum carrier proteins. Endocrinology

107:1451 – 8.

Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL,

Kajstura J, Rubin R, Zoltick P, Baserga R. 1995. The insulin-

like growth factor I receptor protects tumor cells from

apoptosis in vivo. Cancer Res 55:2463 – 9.

Rinderknecht E, Humbel RE. 1978. The amino acid sequence of

human insulin-like growth factor I and its structural homology

with proinsulin. J Biol Chem 253:2769 – 76.

Rosenfeld RG. 2005. The IGF system: new developments relevant

to pediatric practice. Endocr Dev 9:1 – 10.

Rubini M, Hongo A, D’Ambrosio C, Baserga R. 1997. The IGF-I

receptor in mitogenesis and transformation of mouse embryo

cells: role of receptor number. Exp Cell Res 230:284 – 92.

Salmon WD, Daughaday WH. 1957. A hormonally controlled

serum factor which stimulates sulfate incorporation by cartilage

in vitro. J Lab Clin Med 49:825 – 36.

Seino S, Seino M, Nishi S, Bell GI. 1989. Structure of the human

insulin receptor gene and characterization of its promoter. Proc

Natl Acad Sci USA 86:114 – 18.

Sell C, Baserga R, Rubin R. 1995. Insulin-like growth factor I

(IGF-I) and the IGF-I receptor prevent etoposide-induced

apoptosis. Cancer Res 55:303 – 6.

Shier P, Watt VM. 1989. Primary structure of a putative receptor

for a ligand of the insulin family. J Biol Chem 264:14605 – 8.

Tollefsen SE, Thompson K. 1988. The structural basis for insulin-

like growth factor I receptor high affinity binding. J Biol Chem

263:16267 – 73.

Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzeli LM, Dull TJ,

Gray A, Coussens L, Liao Y-C, Tsubokawa M, et al. 1985.

Human insulin receptor and its relationship to the tyrosine

kinase family of oncogenes. Nature 313:756 – 61.

Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubowka M, Collins

C, Henzel W, Lebon T, Kathuria S, Chen F, et al. 1986.

Insulin-like growth factor I receptor primary structure:

comparison with insulin receptor suggests determinants that

define functional specificity. EMBO J 5:2503 – 12.

Werner H, LeRoith D. 2000. New concepts in regulation and

function of the insulin-like growth factors: implications for

understanding normal growth and neoplasia. Cell Mol Life Sci

57:932 – 42.

Werner H, Woloschak M, Stannard B, Shen-Orr Z, Roberts Jr CT,

LeRoith D. 1991. Insulin-like growth factor receptor: Mole-

cular biology, heterogeneity, and regulation. In: LeRoith D,

editor. Insulin-like Growth Factors: Molecular and Cellular

Aspects. Boca Raton, FL: CRC Press; pp 17 – 47.

Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith

D. 1999. Normal growth and development in the absence of

hepatic insulin-like growth factor I. Proc Natl Acad Sci USA

96:7324 – 9.

Yakar S, Sun H, Zhao H, Pennisi P, Toyoshima Y, Setser J,

Stannard B, Scavo L, LeRoith D. 2005. Metabolic effects of

IGF-I deficiency: lessons from mouse models. Pediatr En-

docrinol Rev 3:11 – 19.

Zapf A, Hsu D, Olefsky JM. 1994. Comparison of the intracellular

itineraries of insulin-like growth factor-I and insulin and their

receptors in Rat-1 fibroblasts. Endocrinology 134:2445 – 52.

22 H. Werner et al.

Arc

hive

s of

Phy

siol

ogy

and

Bio

chem

istr

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Alb

erta

on

06/0

6/13

For

pers

onal

use

onl

y.