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
- neurodegenerative disorders
- 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 α-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 α- 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 α- 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).
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).
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)-γ 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 PLCγ1-null mouse embryonic fibroblasts from anoikis-induced apoptosis, but the response could be restored by reexpression of PLCγ 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 D3–1α-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).
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-α (TNFα) 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 TNFα-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.
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.
This work was supported by grants from the Ministero dell'Università e Ricerca (Italy) and the University of Bari to F. Giorgino.
- Copyright © 2008 by American Physiological Society