Insulin-like Growth Factor (IGF) System Proteins

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Insulin-like Growth Factor (IGF) System Proteins

Insulin-like Growth Factor (IGF) System Proteins Background

Insulin-like growth factors are a family of hormones controlling hyperplasia and differentiation throughout the body. The IGF family consists of two hormone ligands: insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2). There are two IGF cell surface receptors: IGF-Type 1 Receptor (IGF-1R) and IGF-Type 2 receptor (IGF-2R, also known as mannose-6-phosphate receptor). The IGF-1R binds IGF-1 with an increased affinity compared to IGF-2; whereas, IGF-2 is bound at an approximately 10-fold decreased affinity. The IGF-2R binds IGF-2 with an increased affinity compared to IGF-1. Insulin binds to IGF-1R at an affinity approximately 100 fold less than IGF-1 and is unable to bind IGF-2R. 
Insulin-like growth factors have sequences and conformation similar to insulin, and are therefore able to bind insulin receptors. There are two insulin receptor isoforms: IR-A and IR-B. Insulin binds to either isoform at approximately the same affinity. IGF-2 also has a high affinity for IR-A, while IGF-1 binds IR-B with decreased affinity compared to insulin. IR-A is expressed at greater levels during gestational development and may be crucial for embryonic growth. It is currently believed that prenatal growth stimulatory effects by IGF-2 are carried out through both IGF-1R and IR-A.

Insulin-like growth factor-1 is a single chain, 70 amino acid peptide cytokine that is homologous to insulin in sequence, translating to three-dimensional structure homology. Along with IGF-2, it is part of a growth factor family termed the IGFs that has effects on most cell types. The IGF-1 gene has been mapped to chromosome 12 in humans and gives rise to two different mRNAs, suggesting a role for mRNA processing in IGF-1 expression. At the cellular level, it is important for progression through the G1/S phase of the cell cycle, and it is known to be a potent inhibitor of apoptosis. It is not surprising, therefore, that disruptions within the IGF-1 axis are observed in many cancers. 
IGF-1 has both endocrine and paracrine/autocrine effects in the body. Its endocrine effects were discovered first, and are therefore the most extensively studied. Endocrine IGF-1 has primarily growth promoting and differentiation functions, and plays a fundamental role in both pre- and post-natal development. Indeed, IGF-1(-/-) mice exhibited a severe growth deficiency of 60% at birth, which was also often lethal shortly after birth, depending on the genetic background of the mice. Circulating IGF-1 is synthesized by the liver, under the control of growth hormone (GH) originating from the anterior pituitary. The “somatomedin hypothesis”, suggested by Daughaday and Collegues, refers to a liver origin of IGF-1 in response to pulsatile GH secretion, resulting in longitudinal bone growth in an endocrine manner. This original hypothesis has been challenged by many studies, including an important study by Lupu et al., which established an IGF-1-independent effect of GH on post-natal body growth. However, this classical endocrine loop does have some well-established and critically important effects, among which are some which are non-overlapping with locally produced IGF-1. One very important role of endocrine IGF-1 is negative feedback on the pituitary. Major phenotypes of loss of this negative feedback result primarily from increased GH levels and include insulin resistance and increased liver size. In addition, humoral IGF-1 has a number of direct effects on a variety of tissues, including insulin sensitizing effects in muscle, liver and fat tissues. It is required for specific brain functions such as mediating the effect of exercise on anxiety and spatial learning, and for clearance of brain β-amyloid. It plays a role in mediating blood pressure and endothelial dysfunction, and is also associated with stimulation of kidney size.

IGF-1 and IGF-2 loss of function mutations 
Both IGF-1 and IGF-2 are important for both prenatal and postnatal growth. Mice lacking functional IGF-1 are approximately 40% smaller than controls at birth. Some of these mice are not viable and die within 6 hours of birth, while some mice survive until adulthood. An IGF-2 loss-of-function mutation was also introduced into a mouse model. Analysis of inheritance indicated heterozygous mice that received a paternally derived IGF-2 mutated allele were approximately 60% smaller (dwarfed) than both wild-type mice and those heterozygous mice that received a maternally derived IGF-2 mutated allele. Mice dwarfed in size were viable, fertile and had similar postnatal growth rates compared to both wild-type and maternally derived heterozygotes. This indicated that IGF-2 is subject to parental imprinting and is particularly important during prenatal growth and development. Because IGF-1 and IGF-2 null mutants result in distinct phenotypes, a hypothesis can be drawn that these growth factors either stimulate separate signaling pathways or their expression is differentially expressed over time. 
Given that IGF-1 and IGF-2 both act through IGF-1R, the current hypothesis is that IGF-1 and IGF-2 are differentially expressed over time. Regulating prenatal growth is the primary function of IGF-2, while IGF-1 is primarily responsible for growth after birth. Skeletal muscle mRNA expression analysis would concur as IGF-2 expression dramatically decreases after birth, while IGF-1 expression increases after birth. However, because IGF-1 and IGF-2 activate the same receptor (IGF-1R), and IGF-1 and IGF-2 null mice are occasionally viable, the growth factors may have some overlapping redundant growth regulating responsibilities.

IGF-1R and IGF-2R 
Mice lacking a functional IGF-1R are approximately 45% smaller than controls and die within minutes of birth due to asphyxiation. Interestingly, IGF-2R, similar to IGF-2, is imprinted, however the maternally derived allele is expressed. Downstream pathways activated by IGF-2R are not well defined. Instead of a traditional signaling cascade, the proposed function of IGF-2R is to bind and degrade IGF-2. Once IGF-2 binds to IGF-2R, the ligand is internalized and degraded, decreasing circulating IGF-2. Mice lacking functional IGF-2R are larger at birth (140% of wild type weight) but usually perish perinatally. Simultaneous deletion of IGF-2 and IGF-2R restores viability, however, mice are born smaller than controls (73.8% of wild type weight). This suggests that excess IGF-2 resulting from the lack of IGF-2R is fatal. Increases in fetal weight and perinatal death in the IGF-2R mutants is believed to be an effect of IGF-2 over activating IGF-1R. The IGF-2R mutants are also rescued through a simultaneous induction of a loss of function IGF-1R mutation. Mice lacking both IGF-1R and IGF-2R have similar birth weights as wild type mice. Triple IGF-2, IGF-2R and IGF-1R loss of function mutants, however, are much smaller at birth (34.4% of wild type weight), but similar to double IGF-1R/IGF-2 mutants (33.6% of wild type weight). Because, mice lacking IGF-1R and IGF-2R have birth weights similar to wild type mice and mice lacking IGF-1R and IGF-2 are significantly smaller, a conclusion can be drawn that IGF-2 interacts with another receptor, such as an insulin receptor isoform, to promote growth. Additionally, IGF-1R can be activated by another ligand; however, when IGF-1R and IGF-2 are both absent at birth weight is reduced. 
Over expression of IGF-2 also results in abnormalities. Beckwith-Wiedemann syndrome, a human disease, has been attributed to loss of imprinting in the IGF-2 gene and results in a 10% increase in birth weight. In contrast to IGF-2R knock-out that also results in increased IGF-2, Beckwith-Wiedemann syndrome is not lethal. This decreased lethality is attributed to the more moderate increase in IGF-2 compared to the increase in IGF-2 after deletion of IGF-2R or transgenic overexpression of IGF-2. Beckwith-Weidmann syndrome, however, is not without symptoms as patients often have growth defects, predisposition to tumors and abnormal body wall closure. In contrast, postnatal IGF-2 overexpression results in increased growth and prolonged increases have been associated with tumor formation. 
Actions of IGF-2R independent of IGF-2 degradation have also been noted. Activation of IGF-2R has also been linked to induction of motility in Rhabdomyosarcoma cells. Therefore, IGF-2R may also be involved in migration of myoblasts or satellite cells during myogenesis and regeneration, respectively. However, to date, no research has been completed focusing on this function of IGF-2R.

IGF Binding Proteins 
The majority of extracellular IGF-1 is bound to specific, high affinity binding proteins, as it is a hydrophilic peptide hormone. Their affinities for IGF-1 are either equal to or greater than that of the IGF-1R, such that their binding capacity establishes an additional level of regulation. Thus, they regulate IGF turnover, transport and tissue distribution. Six have thus far been isolated and characterized, IGFBP-1 to -6, in addition to a low affinity IGFBP-7, which shares only 20 to 25% identity with IGFBP1-6, but contains the highly conserved N-terminal domain. This N-domain contains not only the major IGF binding site, but also the C-domain variable linker, which contributes to both ligand binding and interactions with other proteins. One major interacting protein is the acid-labile subunit (ALS). This subunit is often bound in a ternary complex with IGF-1 and IGFBP-3, a complex which binds up to 80-85% of serum IGF-1. The ALS has the role of retaining the complex in the vascular system, and extending their half-life. Consistent with its role as the major endocrine carrier of the IGF-1 in adults, IGFBP-3 is thought to compete with the IGF-1R for the ligands, thus acting as a growth inhibitor for extravascular tissues. 
In addition to their role as carrier proteins, most IGFBPs have been shown to modulate IGF actions either by inhibiting or potentiating their effects. IGFBP-4 and -6 have consistently been found to inhibit their actions while IGF-1, -2, -3 and -5 can paradoxically do either, depending on the experimental model and method used. Interestingly, accumulating evidence also suggests ligand-independent effects of the IGFBPs. IGFBP-1 was found to bind the α5β1 integrin, thus stimulating cell migration. IGFPB-3, alternatively, has been shown to inhibit cell growth in the absence of IGF-1 and in IGF-1R null cells. Studies have also shown that IGFBP-5, when added to cell cultures lacking endogenous IGF-1, can increase osteoclast formation and bone resorption activity.

IGF Mechanism of Action 
Activation of IGF-1R leads to the activation of two primary signaling cascades: PI3K/AKT and MAPK/ERK. These two pathways are believed to be responsible for opposing processes: proliferation and differentiation. Upon ligand binding, IGF-1R changes conformation, autophosphorylates, and ultimately interacts with Src homology containing protein (Shc), insulin receptor substrate (IRS-1), and other intermediate signaling proteins. Three separate proteins comprise Shc (p46, p52, and p66), and upon interacting with activated IGF-1R, tyrosine residues on the p52 component become heavily phosphorylated. Phosphorylated Shc interacts with the SH2 domain of growth factor receptor bound-2 (Grb2). Activated Shc/GRB2 protein complex binds to Son of Sevenless (Sos) at the SH3 domain on Grb2. The catalytic domain of Sos converts Ras-GDP (inactive form) to Ras-GTP (active). Conversion of inactive to active Ras begins the Ras signaling pathway. 
Once activated, the Ras signaling pathway activates other growth promoting pathways. Ras recruits and activates Raf (serine/threonine kinase) that activates MAPK kinase (MEK1) by phosphorylation. MEK1 then phosphorylates inactive extracellular signal related kinase 1/2 (ERK1/2) protein, found in cytoplasm bound to MEK1. Once activated ERK1/2 disassociates from MEK1 and translocates to the nucleus. ERK1/2 then phosphorylates and activates many growth promoting transcription factors, (ex. c-Myc, NF-IL6, ATF-2).
Similar to Shc, IRS-1 interacts with proteins containing SH2 domains after being phosphorylated by the activated IGF-1R receptor. IRS-1 can interact simultaneously with many SH2 domain-containing proteins such as Grb2, Nck, c-Crk, Syp, and PI3-kinase. Activation of PI3-Kinase leads to activation of AKT (also known as Protein Kinase B). Activation of AKT increases growth by increasing protein synthesis and decreasing protein degradation.

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