AJP - Endo Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 295: E991-E999, 2008. First published August 19, 2008; doi:10.1152/ajpendo.90452.2008
0193-1849/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/5/E991    most recent
90452.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laviola, L.
Right arrow Articles by Giorgino, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laviola, L.
Right arrow Articles by Giorgino, F.

REVIEW

Abnormalities of IGF-I signaling in the pathogenesis of diseases of the bone, brain, and fetoplacental unit in humans

Luigi Laviola, Annalisa Natalicchio, Sebastio Perrini, and Francesco Giorgino

Department of Emergency and Organ Transplantation, Section on Internal Medicine, Endocrinology, and Metabolic Diseases, University of Bari, Bari, Italy

Submitted 20 May 2008 ; accepted in final form 15 August 2008

ABSTRACT

IGF-I action is essential for the regulation of tissue formation and remodeling, bone growth, prenatal growth, brain development, and muscle metabolism. Cellular effects of IGF-I are mediated through the IGF-I receptor, a transmembrane tyrosine kinase that phosphorylates intracellular substrates, resulting in the activation of multiple intracellular signaling cascades. Dysregulation of IGF-I actions due to impairment in the postreceptor signaling machinery may contribute to multiple diseases in humans. This article will review current information on IGF-I signaling and illustrate recent results demonstrating how impaired IGF-I signaling and action may contribute to the pathogenesis of human diseases, including osteoporosis, neurodegenerative disorders, and reduced fetal growth in utero.

insulin-like growth factor I; insulin-like growth factor I receptor; osteoblasts; osteoporosis; neurodegenerative disorders; placenta; intrauterine growth restriction

THE MAIN "ENDOCRINE" ACTION of IGF-I is to mediate the growth-promoting effects of pituitary growth hormone (GH). However, IGF-I-mediated paracrine/autocrine effects are essential in the modulation of cellular growth, proliferation, differentiation, and survival against apoptosis. Although IGF-I may interact with IGF-I, insulin, and hybrid receptors, IGF-I-triggered cellular responses are mediated mostly through the IGF-I receptor signaling pathway and are essential for the regulation of tissue formation and remodeling, bone growth, prenatal growth, brain development, and muscle metabolism. This review will focus on the mechanisms of IGF-I signal transduction and describe specific conditions in which impaired IGF-I signaling and action appear to contribute to the pathogenesis of human diseases.

The IGF System

Insulin-like growth factors. The insulin-like growth factors, including IGF-I, IGF-II, and insulin, are single-chain polypeptides that share a similar secondary structure, with three {alpha}-helixes and three disulphide bonds (110). Despite significant structural similarity, each ligand can result in unique signaling outcomes. For example, IGF-II is unable to compensate for the loss of IGF-I activity in patients with IGF-I deficiency, leading to severe growth and mental retardation (39, 127, 132). Similarly, mice with targeted disruption of the IGF-I or IGF-II genes are born at 60% birth weight compared with wild-type littermates (87, 37). Although in rodents IGF-II is expressed predominantly in fetal life, whereas IGF-I is considered an adult growth factor, this expression pattern is not observed in humans, as both ligands are produced in multiple human tissues throughout life, which is consistent with the concept that IGF-I and IGF-II have potentially divergent roles in human physiology (35).

The IGF-I receptor. Most biological actions of IGF-I are mediated through the type 1 IGF receptor/IGF-I receptor (IGF-IR), a transmembrane tyrosine kinase that is structurally and functionally related to the insulin receptor (IR). Both receptors show a heterotetrameric structure (2 {alpha}- and 2 β-subunits) with an extracellular hormone-binding domain, a transmembrane region, and an intracellular portion that contains the kinase domain and multiple regulatory residues. The IGF-IR and IR are highly homologous in the tyrosine kinase domain (84%) but differ markedly in other regions (e.g., only 22–26% homology in the transmembrane domain and 45% homology in the COOH-terminal domain) (102), and this may contribute to the biological specificity of the two receptors.

The complexity of IGF signaling is increased by the formation of hybrid receptors that result from dimerization of IGF-IR and IR hemireceptors. Each hybrid receptor consists of a single {alpha}- and β-subunit linked by disulfide bonds, which are formed in the Golgi apparatus of cells expressing both the IGF-IR and IR. In some circumstances, hybrid receptors may outnumber homoreceptor molecules at the cell surface. IGF-IR/IR hybrid receptors retain high affinity for IGF-I but exhibit a dramatically decreased affinity for insulin. Thus, the presence of a significant number of hybrid receptors may selectively diminish cellular responsiveness to insulin but not to IGF-I. Indeed, this has been proposed as a mechanism by which upregulation of IGF-IR expression may cause insulin resistance in cells expressing the IR (100).

IGF-binding proteins. The interaction of IGF-I with the IGF-IR can be regulated either positively or negatively by a family of six high-affinity IGF-binding proteins (IGFBPs; IGFBP-1 to -6) (32, 46). Plasma IGFBPs act to increase the circulating half-life and delivery of IGF to tissues (9, 32, 46). In tissues, IGFBPs can both inhibit and potentiate IGF-I action either by sequestering IGF-I from the IGF-IR or by releasing IGF-I to bind to the IGF-IR. IGF-I is released from the complex by either proteolysis of IGFBPs or binding of IGFBPs to the extracellular matrix. IGFBP phosphorylation can also alter the affinity for IGFs (46). IGF-independent actions have recently been described for most IGFBPs and can involve intracellular localization or integrin binding (32, 46).

IGF-I signaling. Upon ligand binding, the intrinsic tyrosine kinase of the IGF-IR is activated, and this results in autophosphorylation of tyrosines on the intracellular portion of the β-subunit, including tyrosine residues in the juxtamembrane and COOH-terminal domains. Once phosphorylated, tyrosine 950 in the juxtamembrane domain can serve as a docking site for several receptor substrates, including the insulin receptor substrates (IRS) 1–4 and Shc (16, 114). These substrates initiate phosphorylation cascades that serve to transmit the IGF-IR signal. Phosphorylated IRS-1 can activate the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to activation of several downstream substrates, including protein kinase B (Akt) (53). Akt phosphorylation, in turn, enhances protein synthesis through mTOR and p70 S6 kinase activation and triggers the antiapoptotic effects of IGF-IR through phosphorylation and inactivation of Bad (106). In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS-1 or Shc leads to recruitment of Ras and activation of the Raf-1/MEK/ERK pathway and downstream nuclear factors, resulting in the induction of cell proliferation (55, 64). Shc may actually compete with IRS-1 for a limited cellular pool of Grb2, and the extent of Shc/Grb2 binding appears to correlate with the amount of insulin-activated ERK and c-fos transcription (136). Therefore, the Shc/Grb2 pathway represents the predominant mechanism activating the Ras/ERK signaling pathway in response to IGF-I. Recent experimental evidence has shown that distinct Shc isoforms exert opposite effects on the ERK signaling cascade. The Shc proteins originate by alternative use of three distinct translation starting points on a longer transcript (p46Shc, p52Shc, and p66Shc) and two translation starting points on a shorter transcript (p46Shc, p52Shc); the two mRNA transcripts are generated by alternative splicing from a single gene (89, 103, 126). Although all three Shc isoforms can be tyrosine phosphorylated upon growth factor stimulation, p46/p52Shc is coupled to growth and survival signals, whereas p66Shc also undergoes serine phosphorylation and mediates proapoptotic responses to oxidative stress (88). Specifically, the p66Shc has been shown to regulate intracellular oxidant levels and hydrogen peroxide-mediated forkhead inactivation (93), effects that are probably relevant to the reported ability of p66Shc to control lifespan in mammals (88) and are unique to this Shc isoform. Therefore, whereas p46/p52Shc triggers the activation of the ERK pathway via Grb2/Sos/Ras, p66Shc has been shown to exert an inhibitory effect on ERK, because reduced expression levels of p66Shc were associated with persistent ERK activation (92). The opposite effects of p46/p52Shc and p66Shc on ERK activation are of pathophysiological significance, since human breast cancer tissues with high p46/p52Shc to p66Shc expression ratios show increased proliferative activity and are associated with poor prognosis (36).

IGF-I receptor activation is also coupled to the stimulation of a family of MAP kinases, besides ERK1/2, including c-Jun NH2-terminal kinase (JNK)-1 and -2 (40) and p38 MAP kinase (59, 112). JNKs phosphorylate the amino terminus of c-Jun, increasing its ability to activate transcription (40). Multiple targets have been identified downstream of the MAP kinases, including ribosomal S6 kinase (Rsk 90), MAPKAP, phospholipase A2, and multiple transcription factors (112). In some cell types, the IGF-IR can also directly phosphorylate the Janus-activated kinases (JAK-1 and -2) that are involved in cytokine-mediated signaling, and JAK proteins may, in turn, phosphorylate IRS-1 (57). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. STAT3 (139), and STAT3 activation in particular, may be essential for the transforming activity of IGF-IR (140).

Excessive and/or inappropriate signaling through the IGF-I receptor cascade is prevented by multiple feedback mechanisms, including Akt/mTOR-dependent IRS-1 degradation and inactivation of IRS proteins through tyrosine dephosphorylation by specific cytoplasmic phosphatases or JNK-induced serine phosphorylation (16).

Other effectors downstream of IGF-IR activation include Src (116), the pp125 focal adhesion kinase that is directly phosphorylated by IGF-IR (8), and the protooncogenes c-Crk II and CrkL (78, 11), which can link IGF-IR to integrin-mediated signaling and the cytoskeleton through p130 Cas and paxillin, thereby regulating cell shape and motility (8, 22). Because intracellular calcium levels increase in response to IGF-I, phospholipase C (PLC)-{gamma} is also thought to be indirectly involved through its products inositol 1,4,5-trisphosphate and 1,2-diacylglycerol (113). This was also demonstrated by the fact that IGF could not rescue PLC{gamma}1-null mouse embryonic fibroblasts from anoikis-induced apoptosis, but the response could be restored by reexpression of PLC{gamma} in these cells (26).

The preferential association of cytoplasmic proteins with the IGF-IR compared with the IR may represent an additional mechanism for signaling specificity. The intracellular protein Grb10, which contains both SH2 and pleckstrin homology consensus sequences, has been cloned as an IR- and IGF-IR-interacting protein (42, 61). Grb10 interacts directly with both the IR and the IGF-IR in vitro, although it appears to associate preferentially with the IR in intact cells (82) due to specific molecular determinants (62). The role of Grb10 remains obscure, with some studies reporting inhibition of receptor function (44, 86, 120) or of specific pathways (90) and others suggesting enhancement of mitogenic responses (98, 128). Interestingly, mutations in Grb10 sequence have been found in two patients with Russell-Silver syndrome, characterized by prenatal and postnatal growth retardation and dysmorphic features, suggesting a modulating role of Grb10 in human growth processes (137).

IGF-I and Bone

The IGF-I system in bone cells. The GH-IGF-I axis provides the main stimulus for bone growth regulation by activating the osteoblast differentiation program, stimulating chondrocyte proliferation at the growth plate, and modulating tubular reabsorption of phosphate and 25-hydroxyvitamin D3–1{alpha}-hydroxylase activity in the kidney (24, 25). The fundamental role of IGF-I in regulating bone formation is demonstrated by analysis of the IGF-I-deficient mouse, which exhibits skeletal malformations, delayed mineralization, reduced chondrocyte proliferation, and increased chondrocyte apoptosis (129). The expression of functional IGF-IR and GH receptors mediating proliferative and differentiative effects has been reported in cultured human osteoblast-like cells (75, 95) and in clonal rat and mouse osteoblast-like cell lines (12, 118). In addition, it has been shown that IGF-I treatment is effective in inducing gene expression for osteoblastic markers independent of age, identifying exogenous IGF-I as a potential beneficial treatment in age-related bone loss (123). IGF-IR expression has been demonstrated also in mature rabbit osteoclasts, as well as human preosteoclasts (70, 45), and IGF-I enhances formation of osteoclast-like cells in long-term bone marrow cultures (66, 74). In contrast, IGF-I has an inhibitory effect on stimulated bone resorption in bone organ cultures (74). Osteoblasts also produce IGFBPs, dependent upon stage of maturation and by stimulation with GH or IGFs. These IGFBPs regulate GH and IGF responses by modulating receptor expression and bioavailability of IGF-I and IGF-II. IGFBP-2 is important as a circulating carrier of IGFs, and IGFBP-2 serum levels correlate with bone mineral density and turnover in humans (4). The effects of IGFBP-2 are complex: female igfbp-2-null mice have increased cortical bone, whereas male igfbp-2 null mice display decreased cortical and trabecular bone secondary to decreased bone formation (38). These observations suggest that IGFBP-2 is required for normal bone formation in male mice and are in agreement with clinical observations indicating correlation between serum IGFBP-2 levels and bone remodeling and anabolic effects following administration of IGF-II/IGFBP-2 in disuse osteoporosis (5, 33). It is also of interest that mechanical loading upregulates the expression of IGF-I and IGFBP-2 transcripts in osteocytes (109). The IGFs increase collagen production and are incorporated into bone matrix bound to IGFBP-5. During osteoclastic resorption, IGF-I and IGF-II are released and may again regulate osteoblastic function, thereby coupling bone resorption and formation. Finally, GH, IGFs, and IGFBPs may all regulate osteoclastic bone resorption through direct and indirect effects on osteoclast differentiation and activation.

IGF-I signaling in bone cells. IGF-I action on bone cells requires the integrity of the IGF-IR signaling pathway. As an example, both IRS-I and IRS-2 are expressed in osteocytes (135). It has recently been proposed that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, and that the integration of these two signals mediates a potent anabolic response to IGF-I in the bone (3, 97). The PI3K/Akt pathway is utilized by IGF-I to decrease osteoblast apoptosis. Sustained activation of ERK1 and ERK2 by IGF-I is also important for the regulation of osteoblast proliferation (55, 138), whereas other MAP kinase family members, such as JNK and p38, seem to be less involved (55, 77).

Abnormalities in IGF-I action and signaling occur in human osteoblasts under conditions of net bone loss. Individuals with insulin deficiency, as exemplified by type 1 diabetic patients, are susceptible to developing osteoporosis (79). Patients with Laron's syndrome caused by IGF-I deficiency are also prone to exhibit this condition (80). A reduction in IGF-I levels is implicated as an important factor in the etiology of evolutional osteoporosis, especially of age-related bone loss (17, 94, 111). Interestingly, although it has been shown that recombinant human IGF-I (rhIGF-I) administration increases osteoblast function in healthy females in whom IGF-I levels and bone turnover were decreased by short-term caloric deprivation (56), rhIGF-I was found to be ineffective in increasing bone mineral density in women with postmenopausal osteoporosis (52). Thus, abnormalities in IGF-I signaling may be responsible for altered IGF-I action on osteoblasts in human osteoporosis. Recently, a comparative analysis of IGF-I signaling was carried out in primary cultures of human osteoblasts isolated from osteoporotic and control bone specimens (105). In the osteoblasts from osteoporotic bone, tyrosine phosphorylation of the IGF-I receptor was found to be increased in the basal state but poorly responsive to IGF-I stimulation. Augmentation of IGF-I receptor phosphorylation in the basal state was associated with increases in tyrosine phosphorylation of IRS-2 and activation of ERK, which were also minimally responsive to IGF-I stimulation. By contrast, phosphorylation levels of IRS-1, Akt, and GSK-3 were similar in the basal state in control and osteoporotic osteoblasts and showed marked increases after IGF-I stimulation in both cell populations, although these responses were significantly lower in the osteoporotic osteoblasts. Specifically, phosphorylation of Akt on Ser473 and Thr308 by IGF-I stimulation was significantly reduced in osteoporotic compared with control cells, leading to decreased GSK-3 phosphorylation. The IGF-I signaling abnormalities in osteoporotic osteoblasts were associated with reduced DNA synthesis both under basal conditions and after stimulation with IGF-I (105). Therefore, abnormalities in IGF-I signaling may represent a novel mechanism for the impaired cell proliferation and decreased bone formation that occur in human osteoporosis (Fig. 1).


Figure 1
View larger version (47K):
[in this window]
[in a new window]

  		Fig. 1. IGF-I signaling and action in human osteoblasts from control subjects or subjects with osteoporosis. The activity of specific signaling molecules is indicated in both the absence and presence of IGF-I. In control osteoblasts (A), exposure to IGF-I results in engagement of insulin receptor substrate (IRS) proteins and activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and Ras/MAPK signaling pathways, leading to increased cell survival and proliferation. In contrast, in osteoblasts from individuals with osteoporosis (B), the IGF-I receptor (IGF-IR) is already activated in the basal state (please note tyrosine phosphorylation of the IGF-IR in osteoblasts from patients with osteoporosis), and this is associated with constitutive activation of the Ras/MAPK signaling pathway, leading to reduced cell proliferation. With exposure to IGF-I, the PI3K/Akt signaling pathway is activated, albeit to a lower level than in control cells, whereas the Ras/MAPK pathway is not significantly affected compared with the basal state, and this is associated with reduced survival and mitogenetic signals. Individual signaling molecules with the phosphorylated amino acid residues are indicated. PDK-1, pyruvate dehydrogenase kinase-1; MEK, MAPK kinase; SOS-1, Son of Sevenless; Tyr, tyrosine; Thr, threonine; Ser, serine.

 
IGF-I and Brain

IGF-I in neurons. IGF-I is highly expressed within the brain and is essential for normal brain development (43, 51). Although the actions of insulin seem to be mostly, if not entirely, related to metabolic control, the actions of IGF-I on the brain are diverse. Glucose utilization is reduced by ~30–60% in the developing igf-1-null brain, with the greatest decrease in structures where IGF-I expression is normally highest (29). The defect in glucose utilization in igf-1 null brains is demonstrable at the nerve terminal level (synaptosomes) in vitro and is completely reversed by IGF-I. IGF-I deficiency also results in decreased postnatal brain growth (10, 29). Furthermore, IGF-I enhances nerve cell metabolism (13) and modulates neuronal excitability (18), two properties that, together with its antiapoptotic actions, may be crucial for the ability of IGF-I to protect nerve cells against insults (21). At tissue level, IGF-I stimulates angiogenesis (63), regulates amyloid load (20), and modulates the activity of neuronal circuitries (23, 96).

IGF-I signaling in brain. IGF-I-induced Akt phosphorylation appears to be linked to both production and translocation of neuronal glucose transporter 4 (GLUT4) from intracellular pools to nerve process membranes in the normal developing brain. In igf-1-null brains, however, GLUT4 immunoreactivity is reduced and GLUT4 mRNA is also decreased in projection neurons (29). Hexokinase activity is significantly reduced in igf-1-null brains, suggesting a role for IGF-I in regulation of brain hexokinase activity, which may also contribute to the decreased glucose utilization in these brains (29). Insulin and IGF-I have both been shown to stimulate the inhibitory serine phosphorylation of GSK-3β in cultured neurons (69). IGF-induced inhibitory phosphorylation of GSK-3β on serine 9 (121) relieves GSK-3β inhibition of glycogen synthase and the translation initiation factor eukaryotic initiation factor 2B (eIF2B), thus promoting glycogen and protein synthesis. Observations in igf-1-null mice provide compelling evidence that GSK-3β is involved in anabolic pathways in brain development (29). Another important GSK-3β target is eIF2B (48), which would also be inhibited by GSK-3β overactivity, contributing to the asthenia affecting igf-1-null neurons. Tau, a microtubule-associated protein involved in neurofilament stabilization, is a GSK-3β substrate. In vitro studies have shown that both insulin and IGF-I inhibit GSK-3β in neural cells, resulting in hyperphosphorylation of tau (69, 84). When hyperphosphorylated, tau is prone to form intracelllular neurofibrillary tangles that contribute to neuronal degeneration and apoptosis (34, 65, 85, 124). Thus, GSK-3β hyperactivity in the igf-1-null brain may contribute not only to hypoplastic neuronal development through reduced anabolic processes but also to increased neuronal loss (28). In addition, activation of the Akt/GSK-3β pathway by both the IGF-IR and estrogen receptor provides an important example of how IGFs and steroids may cooperate to exert neuroprotective actions (50).

Recent evidence indicates that intracellular IGF-I signaling may be compromised in several neurodegenerative diseases. Serum and brain IGF-I levels change in several neurodegenerative conditions in both humans and animal models (15). In addition, the Ser kinase Akt, a critical component of the IGF-I prosurvival signaling pathway, is altered in neurodegenerative diseases such as spinocerebellar ataxia 1 and Huntington's disease (27, 71). Moreover, C2-ceramide, an intracellular lipid generated in response to stimuli associated with neurodegeneration, induces apoptosis and neuronal death in Parkinson's disease by blocking the PI3K/Akt pathway and impairing neuronal metabolism (6a).

Thus, reduced IGF-I concentration and/or action in specific brain areas may contribute to neuronal injury. Inflammation, a common trait in neurodegenerative diseases (134), may further impair survival signals by inducing IGF-I resistance. Since proinflammatory cytokines such as tumor necrosis factor-{alpha} (TNF{alpha}) attenuate insulin/IGF-I signaling by interfering with IRS signaling (125), nerve cells in areas undergoing an inflammatory process may become IGF-I resistant. More recently, IGF-I has been shown to protect oligodendrocyte progenitors against TNF{alpha}-induced damage by activating Akt and inhibiting the mitochondrial apoptotic pathway (101). A similar situation may develop in excitotoxic damage. Overstimulation of neuronal excitatory signaling through excess glutamate underlies several important neurodegenerative processes (72). Because excitotoxic, but not normal, doses of glutamate attenuate IGF-I signaling in vitro and in vivo (49), neurons located in the vicinity ("penumbra") of the excitotoxic lesion lose sensitivity to IGF-I. As an example, the reported development of insulin resistance in Alzheimer's brains (51) is very likely associated with brain IGF-I resistance (73). Other relatively rare neurodegenerative diseases may be due to low IGF-I input to neurons. These include ataxiatelangectasia (AT), in which low levels of IGF-I receptor, apparently caused by mutation of the affected protein, lead to loss of sensitivity to IGF-I in fibroblasts (104). Indeed, AT patients, who have mutations in Atm, a DNA kinase of the PI3K family, show high serum IGF-I levels (15), a characteristic trait of systemic resistance to IGF-I (73). Loss of sensitivity to IGF-I may develop secondary not only to inflammation or excitotoxicity, as mentioned above, but can also be induced by prion infection (99), environmental toxins (14), or ethanol consumption (58). Sequestration of IGF-I by high levels of IGFBPs in lesioned areas, as recently proposed in spinal cord of amyotrophic lateral sclerosis patients (130), may also impede the trophic effects of this peptide. Low serum IGF-I levels associated with aging may also underlie age-associated neurodegeneration, including major diseases such as late-onset Alzheimer's disease (19). Finally, mutations in the Grb10-associated protein GIGYF2 have been very recently reported in familial Parkinson's disease, suggesting a potential role for altered IGF-I signaling also in this neurodegenerative disease (81).

IGF-I and fetoplacental unit. Since IGF-I exerts a key role in fetoplacental growth throughout gestation (47), dysregulation of IGF-I actions due to abnormal expression of IGFs, structural defects in their receptors, or impairment in the postreceptor signaling machinery may contribute to abnormal fetal growth. Low maternal serum IGF-I levels have been related to poor placental function, as indicated by Doppler velocimetry studies of umbilical arteries, rather than to low birth weight (68). Expression levels of both IGF-I and IGF-II were found to be increased in intrauterine growth restriction (IUGR) term placentas (1, 117), whereas immunohistochemistry studies showed a conserved distribution of IGF-I receptor protein in placentas associated with various degrees of IUGR compared with those of normally grown fetuses (67). IGF-I receptor mRNA levels measured by quantitative PCR appeared to be increased in IUGR placentas (1). By contrast, experimentally induced IUGR in rats was characterized by reduced IGF-I receptor levels, measured by evaluating both mRNA levels and total protein content (108). More recently, the hypothesis that IUGR may derive from impaired IGF-I signaling has been tested in multiple experimental settings. Targeted disruption of the igf-1 or igf-1r genes is associated with marked IUGR in mice (7, 107), and partial deletion of the igf-1 gene has been reported to be responsible for IUGR and postnatal growth failure in humans (133). Knockout experiments in mice, in which gene expression of IRS-I or IRS-2 was abrogated in all tissues, also showed growth defects (6, 122, 131). Finally, Akt1-deficient mice showed a 20% reduction in body weight at birth compared with wild-type littermates (31). Discrete abnormalities in the IGF-I signaling pathway were identified in human placentas from pregnancies complicated by IUGR compared with those from normal pregnancies, including reduced protein content of the IGF-I receptor, its major substrate IRS-2, and the serine/threonine kinases Akt and ERK1/2 (83). Interestingly, in IUGR placentas, IRS-2 protein levels were markedly reduced, whereas those of IRS-1 were unchanged, suggesting that the selective downregulation of IRS-2 and its association with PI3K in the IUGR placentas may play important roles in the impaired development of the fetoplacental unit. The impairment of IGF-I receptor/IRS-2 pathway could be responsible for increased apoptotic rates in placental tissue (119), since extensive apoptosis in preimplantation embryos is associated with downregulation of the IGF-I receptor (30). In addition, IUGR placentas feature a marked impairment of the coordinated activation of the MAPKs with reduced p38 and JNK phosphorylation (83), which may play an important role in altering placental angiogenesis, contributing to reduced fetal growth. Targeted disruption of the p38 MAPK gene results in homozygous embryonic lethality because of severe defects in placental development. In particular, p38 mutant placentas display impaired vascularization and insufficient oxygen and nutrient transport as well as increased rates of apoptosis, consistent with a defect in placental angiogenesis (2, 91). In primary human trophoblast, specific activation of JNK in response to placental growth factor protects from serum withdrawal-induced apoptosis (41). Reduced activation of JNK has also been observed in placental tissue from women with preeclampsia (60), which features a defective vascular development of the fetoplacental unit, similar to IUGR pregnancies (76). Interestingly, mice with targeted disruption of the junB gene, a member of the activating protein-1 transcription factor complex, which lies downstream and is activated by JNK, show severe growth retardation in utero, embryonic lethality, and defective development of the fetomaternal vascularization (115). Thus, abnormalities in expression and/or activation of specific IGF-I receptor signaling molecules and multiple members of the MAP kinase family occur in human placentae of IUGR fetuses at delivery. These molecular defects may be responsible for impaired IGF-I responsiveness and appropriate development of the fetoplacental unit, leading to dysregulation of fetal growth in humans.

Conclusions

Although the main "endocrine" action of IGF-I is to mediate the growth-promoting effects of GH, IGF-I-mediated paracrine/autocrine effects are essential in the modulation of cellular growth, proliferation, differentiation, and survival in diverse tissues. Impaired IGF-I signal transduction has been linked to biological abnormalities that characterize multiple pathological conditions (Table 1). The identification of distinct molecular defects in the IGF-I signaling cascade will increase our understanding of the pathogenesis of specific diseases in humans and potentially define targets for novel therapeutical interventions.


View this table:
[in this window]
[in a new window]

  		Table 1. Impairment of IGF-I signaling in bone, brain, and fetoplacental unit and related abnormalities

 
GRANTS

This work was supported by grants from the Ministero dell'Università e Ricerca (Italy) and the University of Bari to F. Giorgino.

FOOTNOTES


Address for reprint requests and other correspondence: F. Giorgino, Dept. of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, and Metabolic Diseases, Univ. of Bari, Piazza Giulio Cesare, 11, I-70124 Bari, Italy (e-mail: f.giorgino{at}endo.uniba.it)

REFERENCES

  1. Abu-Amero SN, Ali Z, Bennett P, Vaughan JI, Moore GE. Expression of the insulin-like growth factors and their receptors in term placentae: a comparison between normal and IUGR births. Mol Reprod Dev 49: 229–235, 1998.[CrossRef][Web of Science][Medline]
  2. Adams RH, Porras A, Alonso G, Jones M, Vintersten K, Panelli S, Valladares A, Perez L, Klein R, Nebreda AR. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell 6: 109–116, 2000.[CrossRef][Web of Science][Medline]
  3. Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y, Tobe K, Takagi H, Azuma Y, Kadowaki T, Nakamura K, Kawaguchi H. Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. J Cell Biol 159: 147–156, 2002.[Abstract/Free Full Text]
  4. Amin S, Riggs BL, Atkinson EJ, Oberg AL, Melton LJ 3rd, Khosla S. A potentially deleterious role of IGFBP-2 on bone density in aging men and women. J Bone Miner Res 19: 1075–1083, 2004.[CrossRef][Web of Science][Medline]
  5. Amin S, Riggs BL, Melton LJ 3rd, Achenbach SJ, Atkinson EJ, Khosla S. High serum IGFBP-2 is predictive of increased bone turnover in aging men and women. J Bone Miner Res 22: 799–807, 2007.[CrossRef][Web of Science][Medline]
  6. Araki E, Lipes MA, Patti ME, Brüning JC, Haag B 3rd, Johnson RS, Kahn CR. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372: 186–190, 1994.[CrossRef][Web of Science][Medline]
  7. Arboleda G, Huang TJ, Waters C, Verkhratsky A, Fernyhough P, Gibson RM. Insulin-like growth factor-1-dependent maintenance of neuronal metabolism through the phosphatidylinositol 3-kinase-Akt pathway is inhibited by C2-ceramide in CAD cells. Eur J Neurosci 25: 3030–3038, 2007.[CrossRef][Web of Science][Medline]
  8. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73–82, 1993.[CrossRef][Web of Science][Medline]
  9. Baron V, Calleja V, Ferrari P, Alengrin F, Van Obberghen E. p125Fak focal adhesion kinase is a substrate for the insulin and insulin-like growth factor-I tyrosine kinase receptors. J Biol Chem 273: 7162–7168, 1998.[Abstract/Free Full Text]
  10. Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 278: E967–E976, 2000.[Abstract/Free Full Text]
  11. Beck KD, Powell-Braxton L, Widmer HR, Valverde J, Hefti F. Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hyppocampal granule and striatal parvalbumin-containing neurons. Neuron 14: 717–730, 1995.[CrossRef][Web of Science][Medline]
  12. Beitner-Johnson D, Le Roith D. Insulin-like growth factor-I stimulates tyrosine phosphorylation of endogenous c-Crk. J Biol Chem 270: 5187–5190, 1995.[Abstract/Free Full Text]
  13. Bennet A, Chen T, Feklman D, Hinzt RL, Rosenfeld RG. Characterization of insulin-like growth factor I receptors in cultured human osteoblast-like cells. J Clin Endocrinol Metab 80: 3483–3488, 1995.[Abstract]
  14. Bondy CA, Cheng CM. Insulin-like growth factor-I promotes neuronal glucose utilization during brain development and repair processes. Int Rev Neurobiol 51: 189–217, 2002.[Web of Science][Medline]
  15. Bulleit RF, Cui H. Methylmercury antagonizes the survival-promoting activity of insulin-like growth factor on developing cerebellar granule neurons. Toxicol Appl Pharmacol 153: 161–168, 1998.[CrossRef][Web of Science][Medline]
  16. Busiguina S, Fernandez AM, Barrios V, Clark R, Tolbert DL, Berciano J, Torres-Aleman I. Neurodegeneration is associated to changes in serum insulin-like growth factors. Neurobiol Dis 7: 657–665, 2000.[CrossRef][Web of Science][Medline]
  17. Butler AA, Yakar S, Gewolb IH, Karas M, Okubo Y, LeRoith D. Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. Comp Biochem Physiol B Biochem Mol Biol 121: 19–26, 1998.[CrossRef][Medline]
  18. Canalis E. Insulin-like growth factors and osteoporosis. Bone 21: 215–216, 1997.[CrossRef][Medline]
  19. Carro E, Nunez A, Busiguina S, Torres-Aleman I. Circulating insulin-like growth factor I mediates effects of exercise on the brain. J Neurosci 20: 2926–2933, 2000.[Abstract/Free Full Text]
  20. Carro E, Torres-Aleman I. Insulin-like growth factor I and Alzheimer's disease: therapeutic prospects? Expert Rev Neurother 4: 79–86, 2004.[Medline]
  21. Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 8: 1390–1397, 2002.[CrossRef][Web of Science][Medline]
  22. Carro E, Trejo JL, Nunez A, Torres-Aleman I. Brain repair and neuroprotection by serum insulin-like growth factor I. Mol Neurobiol 27: 153–162, 2003.[CrossRef][Web of Science][Medline]
  23. Casamassima A, Rozengurt E. Insulin-like growth factor-I stimulates tyrosine phosphorylation of p130(Cas), focal adhesion kinas, and paxillin. Role of phosphatidylinositol 3'-kinase and formation of a p130(Cas)Crk complex. J Biol Chem 273: 26149–26156, 1998.[Abstract/Free Full Text]
  24. Castro-Alamancos MA, Torres-Aleman I. Long-term depression of glutamate-induced gamma-aminobutyric acid release in cerebellum by insulin-like growth factor I. Proc Natl Acad Sci USA 90: 7386–7390, 1993.[Abstract/Free Full Text]
  25. Caverzasio J, Bonjour JP, Montessuit C. Stimulatory effect of insulin-like growth factor-I on renal Pi tran sport and plasma 1,25-dihydroxyvitaminD3. Endocrinology 127: 453–459, 1990.[Abstract/Free Full Text]
  26. Caverzasio J, Bonjour JP. Insulin-like growth factor I stimeulates Na-dependent Pi transport in cultured kidney cells. Am J Physiol Renal Fluid Electrolyte Physiol 257: F712–F717, 1989.[Abstract/Free Full Text]
  27. Chattopadhyay A, Carpenter G. PLC-g1 is required for IGF-I protection from cell death induced by loss of extracellular matrix adhesion. J Cell Sci 115: 2233–2239, 2002.[Abstract/Free Full Text]
  28. Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EM, Orr HT, Botas J, Zoghbi HY. Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113: 457–468, 2003.[CrossRef][Web of Science][Medline]
  29. Cheng CM, Chen M, Tseng V, Bondy CA. Endogenous IGF-I enhances cell survival in the postnatal dentate gyrus. J Neurosci Res 64: 341–347, 2001.[CrossRef][Web of Science][Medline]
  30. Cheng CM, Reinhardt RR, Lee WH, Joncas G, Patel SC, Bondy CA. Insulin-like growth factor I regulates developing brain glucose metabolism. Proc Natl Acad Sci USA 97: 10236–10241, 2000.[Abstract/Free Full Text]
  31. Chi MM, Schlein AL, Moley KH. High insulin-like growth factor 1 (IGF-1) and insulin concentrations trigger apoptosis in the mouse blastocyst via down-regulation of the IGF-1 receptor. Endocrinology 141: 4784–4792, 2000.[Abstract/Free Full Text]
  32. Cho H, Thorvaldsen JL, Chu Q, Feng F, Birnbaum MJ. Akt1/PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 276: 38349–38352, 2001.[Abstract/Free Full Text]
  33. Clemmons DR. Use of mutagenesis to probe IGF-binding protein structure/function relationships. Endocr Rev 22: 800–817, 2001.[Abstract/Free Full Text]
  34. Conover CA, Johnstone EW, Turner RT, Evans GL, John Ballard FJ, Doran PM, Khosla S. Subcutaneous administration of insulin-like growth factor (IGF)-II/IGF binding protein-2 complex stimulates bone formation and prevents loss of bone mineral density in a rat model of disuse osteoporosis. Growth Horm IGF Res 12: 178–183, 2002.[CrossRef][Web of Science][Medline]
  35. Crowder RJ, Freeman RS. Glycogen synthase kinase-3 beta activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal. J Biol Chem 275: 34266–34271, 2000.[Abstract/Free Full Text]
  36. Daughday WH, Rotwein P. Insulin-like growth factors I and II: peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10: 68–91, 1989.[Abstract/Free Full Text]
  37. Davol PA, Bagdasaryan R, Elfenbein GJ, Maizel AL, Frackelton AR Jr. Shc proteins are strong, independent prognostic markers for both node-negative and node-positive primary breast cancer. Cancer Res 63: 6772–6783, 2003.[Abstract/Free Full Text]
  38. De Chiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 345: 78–80, 1990.[CrossRef][Web of Science][Medline]
  39. DeMambro VE, Clemmons D, Beamer WG, Bouxsein ML, Canalis E, Rosen CJ. Serum IGFBP-2 (IGF binding protein-2) is a marker of bone turnover; in vivo evidence from the IGFBP-2 null male mouse. J Bone Miner Res 22: S71, 2007.
  40. Denley A, Wang CC, McNeil KA, Walenkamp MJ, van Duyvenvoorde H, Wit JM, Wallace JC, Norton RS, Karperien M, Forbes BE. Structural and functional characteristics of the Val44Met insulin-like growth factor I missense mutation: correlation with effects on growth and development. Mol Endocrinol 19: 711–721, 2005.[Abstract/Free Full Text]
  41. Derijard B, Hibi M, Wu I, Barret T, Su B, Deng T, Karin M, Davis RJ. JNK1: a protein kinase stimulated by UV light and ha-Ras that binds and phosphorylates the C-Jun activation domain. Cell 76: 1025–1037, 1994.[CrossRef][Web of Science][Medline]
  42. Desai J, Holt-Shore V, Torry RJ, Caudle MR, Torry DS. Signal transduction and biological function of placenta growth factor in primary human trophoblast. Biol Reprod 60: 887–892, 1999.[Abstract/Free Full Text]
  43. Dey BR, Frick K, Lopaczynski W, Nissley SP, Furlanetto RW. Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10. Mol Endocrinol 10: 631–641, 1996.[Abstract/Free Full Text]
  44. Dore S, Kar S, Quirion R. Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases. Trends Neurosci 20: 326–331, 1997.[CrossRef][Web of Science][Medline]
  45. Dufresne AM, Smith RJ. The adapter protein GRB10 is an endogenous negative regulator of insulin-like growth factor signaling. Endocrinology 146: 4399–4409, 2005.[Abstract/Free Full Text]
  46. Fiorelli G, Formigli L, Zecchi OS, Gori F, Falchetti A, Morelli A, Tanini A, Benvenuti S, Brandi ML. Characterization and function of the receptor for IGF-I in human preosteoclastic cells. Bone 18: 269–276, 1996.[CrossRef][Web of Science][Medline]
  47. Firth SM, Baxter RC. Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 23: 824–854, 2002.[Abstract/Free Full Text]
  48. Fowden AL. The insulin-like growth factors and feto-placental growth. Placenta 24: 803–812, 2003.[CrossRef][Web of Science][Medline]
  49. Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359: 1–16, 2001.[CrossRef][Web of Science][Medline]
  50. Garcia-Galloway E, Arango C, Pons S, Torres-Aleman I. Glutamate excitotoxicity attenuates insulin-like growth factor I pro-survival signaling. Mol Cell Neurosci 24: 1027–1037, 2003.[CrossRef][Web of Science][Medline]
  51. Garcia-Segura LM, Sanz A, Mendez P. Cross-talk between IGF-I and estradiol in the brain: focus on neuroprotection. Neuroendocrinology 84: 275–279, 2006.[CrossRef][Web of Science][Medline]
  52. Gasparini L, Netzer WJ, Greengard P, Xu H. Does insulin dysfunction play a role in Alzheimer's disease? Trends Pharmacol Sci 23: 288–293, 2002.[CrossRef][Medline]
  53. Ghiron LJ, Thompson JL, Holloway L, Hintz RL, Butterfield GE, Hoffman AR, Marcus R. Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. J Bone Miner Res 10: 1844–1852, 1995.[Web of Science][Medline]
  54. Giorgetti S, Ballotti R, Kowalski-Chauvel A, Tartare S, Van Obberghen E. The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinosotol 3-kinase in vitro. J Biol Chem 268: 7358–7364, 1993.[Abstract/Free Full Text]
  55. Grey A, Chen Q, Xu X, Callon K, Cornish J. Parallel phosphatidylinositol-3 kinase and p42/44 mitogen-activated protein kinase signalling pathways subserve the mitogenic and antiapoptotic actions of insulin-like growth factor I in osteoblastic cells. Endocrinology 144: 4886–4893, 2003.[Abstract/Free Full Text]
  56. Grinspoon S, Baum H, Lee K, Anderson E, Herzog D, Klibanski A. Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J Clin Endocrinol Metab 81: 3864–3870, 1996.[Abstract/Free Full Text]
  57. Gual P, Baron V, Lequoy V, Van Obberghen E. Interaction of Janus kinases JAK-1 and JAK-2 with the insulin receptor and the insulin-like growth factor-I receptor. Endocrinology 139: 884–893, 1998.[Abstract/Free Full Text]
  58. Hallak H, Seiler AE, Green JS, Henderson A, Ross BN, Rubin R. Inhibition of insulin-like growth factor-I signaling by ethanol in neuronal cells. Alcohol Clin Exp Res 25: 1058–1064, 2001.[CrossRef][Web of Science][Medline]
  59. Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808–811, 1994.[Abstract/Free Full Text]
  60. Hannke-Lohmann A, Pildner von Steinburg S, Dehne K, Benard V, Kolben M, Schmitt M, Lengyel E. Downregulation of a mitogen-activated protein kinase signaling pathway in the placentas of women with preeclampsia. Obstet Gynecol 96: 582–587, 2000.[CrossRef][Web of Science][Medline]
  61. Hansen H, Svensson U, Zhu J, Laviola L, Giorgino F, Wolf G, Smith RJ, Riedel H. Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. J Biol Chem 271: 8882–8886, 1996.[Abstract/Free Full Text]
  62. He W, Rose DW, Olefsky JM, Gustafson TA. Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. J Biol Chem 273: 6860–6867, 1998.[Abstract/Free Full Text]
  63. Hellstrom A, Carlsson B, Niklasson A, Segnestam K, Boguszewski M, de Lacerda L, Savage M, Svensson E, Smith L, Weinberger B, Albertssen WK, Laron Z. IGF-I is critical for normal vascularization of the human retina. J Clin Endocrinol Metab 87: 3413–3416, 2002.[Abstract/Free Full Text]
  64. Hermanto U, Zong CS, Wang LH. Inhibition of mitogen-activated protein kinase kinase selectively inhibits cell proliferation in human breast cancer cells displaying enhanced insulin-like growth factor I-mediated mitogen-activated protein kinase activation. Cell Growth Differ 11: 655–664, 2000.[Abstract/Free Full Text]
  65. Hetman M, Cavanaugh JE, Kimelman D, Xia Z. Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20: 2567–2574, 2000.[Abstract/Free Full Text]
  66. Hill PA, Reynolds JJ, Meikle MC. Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function. Endocrinology 136: 124–131, 1995.[Abstract]
  67. Holmes R, Porter H, Newcomb P, Holly JM, Soothill P. An immunohistochemical study of type I insulin-like growth factor receptors in the placentae of pregnancies with appropriately grown or growth restricted fetuses. Placenta 20: 325–330, 1999.[CrossRef][Web of Science][Medline]
  68. Holmes RP, Holly JM, Soothill PW. A prospective study of maternal serum insulin-like growth factor-I in pregnancies with appropriately grown or growth restricted fetuses. Br J Obstet Gynaecol 105: 1273–1278, 1998.[Web of Science][Medline]
  69. Hong M, Lee VM. Insulin and insulin-like growth factor-I regulate tau phosphorylation in cultured human neurons. J Biol Chem 272: 19547–19553, 1997.[Abstract/Free Full Text]
  70. Hou P, Sato T, Hofstetter W, Foged NT. Identification and characterization of the insulin-like growth factor I receptor in mature rabbit osteoclasts. J Bone Miner Res 12: 534–540, 1997.[CrossRef][Web of Science][Medline]
  71. Humbert S, Bryson EA, Cordelières FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2: 831–837, 2002.[CrossRef][Web of Science][Medline]
  72. Ikonomidou C, Turski L. Excitotoxicity and neurodegenerative diseases. Curr Opin Neurol 8: 487–497, 1995.[CrossRef][Web of Science][Medline]
  73. Jain S, Golde DW, Bailey R, Geffner ME. Insulin-like growth factor-I resistance. Endocr Rev 19: 625–646, 1998.[Abstract/Free Full Text]
  74. Jonsson KB, Wiberg K, Ljunghall S, Ljunggren. Insulin-like growth factor I does not stimulate bone resorption in cultured neonatal mouse calvarial bones. Calcif Tissue Int 59: 366–370, 1996.[CrossRef][Web of Science][Medline]
  75. Kassem M, Blum W, Ristelli J, Mosekilde L, Eriksen EF. Growth hormone stimulates proliferation and differentiation of normal human osteoblast-like cells in vitro. Calcif Tissue Int 52: 222–226, 1993.[CrossRef][Web of Science][Medline]
  76. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 93: 1049–1059, 1986.[Web of Science][Medline]
  77. Kiepe D, Ciarmatori S, Hoeflich A, Wolf E, Tonshoff B. Insulin-like growth factor (IGF)-I stimulates cell proliferation and induces IGF binding protein (IGFBP)-3 and IGFBP-5 gene expression in cultured growth plate chondrocytes via distinct signaling pathways. Endocrinology 146: 3096–3104, 2005.[Abstract/Free Full Text]
  78. Koval AP, Karas M, Zick Y, LeRoith D. Interplay of the proto-oncogene proteins CrkL and CrkII in insulin-like growth factor-I receptor-mediated signal transduction. J Biol Chem 273: 14780–14787, 1998.[Abstract/Free Full Text]
  79. Krakauer JC, McKenna MJ, Rao DS, Whitehouse FW. Bone mineral density in diabetes. Diabetes Care 20: 1339–1340, 1997.[Web of Science][Medline]
  80. Laron Z. The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome. J Clin Endocrinol Metab 84: 4397–4404, 1999.[Abstract/Free Full Text]
  81. Lautier C, Goldwurm S, Durr A, Giovannone B, Tsiaras WG, Pezzoli G, Brice A, Smith RJ. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet 82: 822–833, 2008.[CrossRef][Web of Science][Medline]
  82. Laviola L, Giorgino F, Chow JC, Baquero JA, Hansen H, Ooi J, Zhu J, Riedel H, Smith RJ. The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. J Clin Invest 99: 830–837, 1997.[Web of Science][Medline]
  83. Laviola L, Perrini S, Belsanti G, Natalicchio A, Montrone C, Leonardini A, Vimercati A, Scioscia M, Selvaggi L, Giorgino R, Greco P, Giorgino F. Intrauterine growth restriction in humans is associated with abnormalities in placental insulin-like growth factor signaling. Endocrinology 146: 1498–1505, 2005.[Abstract/Free Full Text]
  84. Lesort M, Johnson GV. Insulin-like growth factor-I and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience 99: 305–316, 2000.[CrossRef][Web of Science][Medline]
  85. Li M, Wang X, Meintzer MK, Laessig T, Birnbaum MJ, Heidenreich KA. Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol Cell Biol 20: 9356–9363, 2000.[Abstract/Free Full Text]
  86. Liu F, Roth RA. Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function. Proc Natl Acad Sci USA 92: 10287–10291, 1995.[Abstract/Free Full Text]
  87. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-I) and type I IGF receptor (IgfIr). Cell 75: 59–72, 1993.[Web of Science][Medline]
  88. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402: 309–313, 1999.[CrossRef][Web of Science][Medline]
  89. Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KM, Superti-Furga G, Pawson T, Di Fiore PP, Lanfrancone L, Pelicci PG. Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway. EMBO J 16: 706–716, 1997.[CrossRef][Web of Science][Medline]
  90. Mounier C, Lavoie L, Dumas V, Mohammad-Ali K, Nantel A, Bergeron JJ, Thomas DY, Posner BI. Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway. Mol Cell Endocrinol 173: 15–27, 2001.[CrossRef][Web of Science][Medline]
  91. Mudgett JS, Ding J, Guh-Siesel L, Chartrain NA, Yang L, Gopal S, Shen MM. Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci USA 97: 10454–10459, 2000.[Abstract/Free Full Text]
  92. Natalicchio A, Laviola L, De Tullio C, Renna LA, Montrone C, Perrini S, Valenti V, Procino G, Svelto M, Giorgino F. Role of the p66Shc isoform in insulin-like growth factor I receptor signaling through MEK/Erk and regulation of actin cytoskeleton in rat myoblasts. J Biol Chem 279: 43900–43909, 2004.[Abstract/Free Full Text]
  93. Nemoto S, Finkel T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295: 2450–2452, 2002.[Abstract/Free Full Text]
  94. Nicolas V, Prewett A, Bettica P, Mohan S, Finkelman RD, Baylink DJ, Farley JR. Age-related decreases in insulin-like growth factor-I and transforming growth factor-beta in femoral cortical bone from both men and women: implications for bone loss with aging. J Clin Endocrinol Metab 78: 1011–1016, 1994.[Abstract]
  95. Nilsson A, Swolin D, Enerback S, Ohlsson C. Expression of functional growth hormone receptors in cultured human osteoblast-like cells. J Clin Endocrinol Metab 80: 3483–3488, 1995.[Abstract]
  96. Nunez A, Carro E, Torres-Aleman I. Insulin-like growth factor I modifies electrophysiological properties of rat brain stem neurons. J Neurophysiol 89: 3008–3017, 2003.[Abstract/Free Full Text]
  97. Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K, Azuma Y, Ohta T, Kadowaki T, Nakamura K, Kawaguchi H. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J Clin Invest 105: 935–943, 2000.[Web of Science][Medline]
  98. O'Neill TJ, Rose DW, Pillay TS, Hotta K, Olefsky JM, Gustafson TA. Interaction of a GRB-IR splice variant (a human GRB10 homolog) with the insulin and insulin-like growth factor I receptors. Evidence for a role in mitogenic signaling. J Biol Chem 271: 22506–22513, 1996.[Abstract/Free Full Text]
  99. Ostlund P, Lindergren H, Pettersson C, Bedecs K. Upregulation of functionally impaired insulin-like growth factor-I receptor in scrapie infected neuroblastoma cells. J Biol Chem 276: 36110–36115, 2001.[Abstract/Free Full Text]
  100. Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 277: 39684–39695, 2002.[Abstract/Free Full Text]
  101. Pang Y, Zheng B, Fan LW, Rhodes PG, Cai Z. IGF-1 protects oligodendrocyte progenitors against TNFalpha-induced damage by activation of PI3K/Akt and interruption of the mitochondrial apoptotic pathway. Glia 55: 1099–1107, 2007.[CrossRef][Web of Science][Medline]
  102. Pedrini MT, Giorgino F, Smith RJ. cDNA cloning of the rat IGF I receptors: structural analysis of rat and human IGF I and insulin receptors reveals differences in alternative splicing and receptor-specific domain conservation. Biochem Biophys Res Commun 202: 1038–1046, 1994.[CrossRef][Web of Science][Medline]
  103. Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Grignani F, Pawson T, Pelicci PG. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70: 93–104, 1992.[CrossRef][Web of Science][Medline]
  104. Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci USA 98: 1676–1681, 2001.[Abstract/Free Full Text]
  105. Perrini S, Natalicchio A, Laviola L, Cignarelli A, Melchiorre M, De Stefano F, Caccioppoli C, Leonardini A, Martemucci S, Belsanti G, Miccoli S, Ciampolillo A, Corrado A, Cantatore FP, Giorgino R, Giorgino F. Abnormalities of insulin-like growth factor-I signaling and impaired cell proliferation in osteoblasts from subjects with osteoporosis. Endocrinology 149: 1302–1313, 2008.[Abstract/Free Full Text]
  106. Petley T, Graff K, Jiang W, Yang H, Florini J. Variation among cell types in the signaling pathways by which IGF-I stimulates specific cellular responses. Horm Metab Res 31: 70–76, 1999.[Web of Science][Medline]
  107. Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, Gillett N, Stewart TA. IGF-I is required for normal embryonic growth in mice. Genes Dev 7: 2609–2617, 1993.[Abstract/Free Full Text]
  108. Reid GJ, Flozak AS, Simmons RA. Placental expression of insulin-like growth factor receptor-1 and insulin receptor in the growth-restricted fetal rat. J Soc Gynecol Investig 9: 210–214, 2002.[Web of Science][Medline]
  109. Reijnders CM, Bravenboer N, Holzmann PJ, Bhoelan F, Blankenstein MA, Lips P. In vivo mechanical loading modulates insulin-like growth factor binding protein-2 gene expression in rat osteocytes. Calcif Tissue Int 80: 137–143, 2007.[CrossRef][Web of Science][Medline]
  110. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin. J Biol Chem 253: 2769–2776, 1978.[Abstract/Free Full Text]
  111. Rosen CJ. Insulin-like growth factor I and bone mineral density: experience from animal models and human observational studies. Best Pract Res Clin Endocrinol Metab 18: 423–435, 2004.[CrossRef][Medline]
  112. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Liamazares A, Zamanillo D, Hunt T, Nebreda AR. A novel kinase cascade triggered by stress and heat shock that stimulates MAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78: 1027–1037, 1994.[CrossRef][Web of Science][Medline]
  113. Rubin R, Baserga R. Insulin-like growth factor-I receptor. Its role in cell proliferation, apoptosis, and tumorigenicity. Lab Invest 73: 311–331, 1995.[Web of Science][Medline]
  114. Samani AA, Brodt P. The receptor for the type I insulin-like growth factor and its ligands regulate multiple cellular functions that impact on metastasis. Surg Oncol Clin N Am 10: 289–312, 2001.[Medline]
  115. Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF. JunB is essential for mammalian placentation. EMBO J 18: 934–948, 1999.[CrossRef][Web of Science][Medline]
  116. Sekharam M, Nasir A, Kaiser HE, Coppola D. Insulin-like growth factor I receptor activates c-SRC and modifies transformation and motility of colon cancer in vitro. Anticancer Res 23: 1517–1524, 2003.[Web of Science][Medline]
  117. Sheikh S, Satoskar P, Bhartiya D. Expression of insulin-like growth factor-I and placental growth hormone mRNA in placentae: a comparison between normal and intrauterine growth retardation pregnancies. Mol Hum Reprod 7: 287–292, 2001.[Abstract/Free Full Text]
  118. Slootweg MC, Salles JP, Ohlsson C, de Vries CP, Engelbregt MJ, Netelenbos JC. Growth hormone binds to a single high affinity receptor site on mouse osteoblasts: modulation by retinoic acid and cell differentiation. J Endocrinol 150: 465–472, 1996.[Abstract/Free Full Text]
  119. Smith SC, Baker PN, Symonds EM. Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 177: 1395–1401, 1997.[CrossRef][Web of Science][Medline]
  120. Stein EG, Gustafson TA, Hubbard SR. The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors. FEBS Lett 493: 106–111, 2001.[CrossRef][Web of Science][Medline]
  121. Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, Birnbaum MJ. The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. J Biol Chem 274: 17934–17940, 1999.[Abstract/Free Full Text]
  122. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, Sekihara H, Yoshioka S, Horikoshi H, Furata Y, Ikawa Y, Kasuga M, Yazaki Y, Aizawa S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372: 182–186, 1994.[CrossRef][Web of Science][Medline]
  123. Tanaka H, Quarto R, Williams S, Barnes J, Liang CT. In vivo and in vitro effects of insulin-like growth factor I (IGF-I) on femoral mRNA expression in old rats. Bone 15: 647–653, 1994.[CrossRef][Medline]
  124. Tong N, Sanchez JF, Maggirwar SB, Ramirez SH, Guo H, Dewhurst S, Gelbard HA. Activation of glycogen synthase kinase 3 beta (GSK-3beta) by platelet activating factor mediates migration and cell death in cerebellar granule neurons. Eur J Neurosci 13: 1913–1922, 2001.[CrossRef][Web of Science][Medline]
  125. Venters HD, Tang Q, Liu Q, VanHoy RW, Dantzer R, Kelley KW. A new mechanism of neurodegeneration: a proinflammatory cytokine inhibits receptor signaling by a survival peptide. Proc Natl Acad Sci USA 96: 9879–9884, 1999.[Abstract/Free Full Text]
  126. Ventura A, Luzi L, Pacini S, Baldari CT, Pelicci PG. The p66Shc longevity gene is silenced through epigenetic modifications of an alternative promoter. J Biol Chem 277: 22370–22376, 2002.[Abstract/Free Full Text]
  127. Walenkamp MJ, Karperien M, Pereira AM, Hilhorst-Hofstee Y, van Doorn J, Chen JW, Mohan S, Denley A, Forbes B, van Duyvenvoorde HA, van Thiel SW, Sluimers CA, Bax JJ, de Laat JA, Breuning MB, Romijn JA, Wit JM. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab 90: 2855–2864, 2005.[Abstract/Free Full Text]
  128. Wang J, Dai H, Yousaf N, Moussaif M, Deng Y, Boufelliga A. Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I, and insulin-mediated mitogenesis. Mol Cell Biol 19: 6217–6228, 1999.[Abstract/Free Full Text]
  129. Wang Y, Nishida S, Sakata T, Elalieh HZ, Chang W, Halloran BP, Doty SB, Bikle DD. Insulin-like growth factor-I is essential for embryonic bone development. Endocrinology 147: 4753–4761, 2006.[Abstract/Free Full Text]
  130. Wilczak N, de Vos RA, De Keyser J. Free insulin-like growth factor (IGF)-I and IGF binding proteins 2, 5, and 6 in spinal motor neurons in amyotrophic lateral sclerosis. Lancet 361: 1007–1011, 2003.[CrossRef][Web of Science][Medline]
  131. Withers DJ, Burks DJ, Towery HH, Altamuro SL, Flint CL, White MF. IRS-2 coordinates IGF-1 receptor-mediated β-cell development and peripheral insulin signalling. Nat Genet 23: 32–40, 1999.[Web of Science][Medline]
  132. Woods KA, Camacho-Hübner C, Barter D, Clark AJ, Savage MO. Insulin-like growth factor I gene deletion causing intrauterine growth retardation and severe short stature. Acta Paediatr Suppl 423: 39–45, 1997.[Medline]
  133. Woods KA, Camacho-Hübner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335: 1363–1367, 1996.[Free Full Text]
  134. Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease—a double-edged sword. Neuron 35: 419–432, 2002.[CrossRef][Web of Science][Medline]
  135. Yamaguchi M, Ogata N, Shinoda Y, Akune T, Kamekura S, Terauchi Y, Kadowaki T, Hoshi K, Chung UI, Nakamura K, Kawaguchi H. Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice. Endocrinology 146: 2620–2628, 2005.[Abstract/Free Full Text]
  136. Yamauchi K, Pessin JE. Insulin receptor substrate-1 (IRS-1) and Shc compete for a limited pool of Grb2 in mediating insulin down-stream signaling. J Biol Chem 269: 31107–31114, 1994.[Abstract/Free Full Text]
  137. Yoshihashi H, Maeyama K, Kosaki R, Ogata T, Tsukahara M, Goto Y, Hata J, Matsuo N, Smith RJ, Kosaki K. Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. Am J Hum Genet 67: 476–482, 2000.[CrossRef][Web of Science][Medline]
  138. Zhang W, Lee JC, Kumar S, Gowen M. ERK pathway mediates the activation of Cdk2 in IGF-1-induced proliferation of human osteosarcoma MG-63 cells. J Bone Miner Res 14: 528–535, 1999.[CrossRef][Web of Science][Medline]
  139. Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem 275: 15099–15105, 2000.[Abstract/Free Full Text]
  140. Zong CS, Zeng L, Jiang Y, Sadowski HB, Wang LH. Stat3 plays an important role in oncogenic Ros- and insulin-like growth factor I receptor-induced anchorage-independent growth. J Biol Chem 273: 28065–28072, 1998.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
295/5/E991    most recent
90452.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Laviola, L.
Right arrow Articles by Giorgino, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Laviola, L.
Right arrow Articles by Giorgino, F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.