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Growth Hormone (GH) and Insulin-Like Growth Factor-1 (IGF-1)
The somatomedins, or insulin-like growth factors (IGFs), comprise a family of peptides that play important roles in mammalian growth and development. IGF-1 mediates many of the growth-promoting effects of growth hormone. Diabetes leads to decreased hepatic production of IGF-1 and the subsequent decrease in serum IGF-1 leads to an excess in growth hormone secretion (Janssen et al 2000). The increase in growth hormone can, in turn, stimulate local IGF1 pathways in other tissues (i.e. the kidney). IGF-1 in vitro has been shown to increase mesangial cell proliferation (Conti et al 1988). Mesangial cells from nonobese diabetic (NOD) mice secrete increased IGF-1 (Elliott et al 1993), and the consequent reduction in MMP-2 activity (Lupia et al 1999) is thought to lead to glomerular ECM accumulation. Increased renal IGF-1 could be caused by changes in renal IGF-1 receptors and IGF-1 binding proteins, rather than by increased local kidney IGF-1 production (Flyvbjerg et al 1994, Gronbaek et al 1996). IGF1 and IGF1R genes have been utilized as candidates for low birth weight, insulin resistance, and type 2 DM (Rasmussen et al 2000). In 82 Danish families with type 2 DM, no mutations were identified in diabetic subjects that had changes in the amino acid sequence in the IGF1 or IGF1R genes. This failure to identify functional variants segregating with disease suggested that variability in the coding regions of IGF1 and IGF1R do not associate with reduced birth weight, insulin sensitivity index, or type 2 DM. There is little evidence suggesting that polymorphisms in the IGF1 locus contribute to risk of DN, despite compelling roles for IGF-1 in pathogenesis and treatment.
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The insulin-like growth factor 1 receptor (IGF1-R) is overexpressed in many tumour cell lines [6–8] with IGF1-R activation being shown to enhance invasion and increase resistance to apoptosis in colonic cancer cells [9]. Our understanding of the control of IGF1-R activation is complicated by the fact that the activity of IGF is also highly dependent upon its interaction with various IGF binding proteins that are, in turn, controlled by interleukins [10]. Because of its probable relevance to tumour pathophysiology, various approaches are being tested to manipulate these systems. For example, the conjugated linoleic acid has been known for some time to possess chemotheraputic properties in a variety of cancer models. One mechanism for this might be downregulation of IGF1-R signaling, via the phosphoinositide 3-kinase/Akt and extracellular-regulated kinase-1/2 pathways [11]. An additional approach that has potential clinical relevance is the recent development of a monoclonal antibody that binds specifically to the human IGF1-R and inhibits cancer cell proliferation in vitro [12•].
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Insulin-Like Growth Factors (IGFs)
Among growth factors, insulin-like growth factors (IGFs) play a pivotal role in stimulating endometrial proliferation. Studies using mice lacking IGF1 revealed that in the absence of this growth factor, the uteri are hypotrophic. Further studies revealed a dramatic upregulation of IGF1 followed by phosphorylation of insulin-like growth factor 1 receptor (IGF1R) expressed in the uterine epithelium in response to treatment with estrogen. Activation of IGF1 signaling leads to nuclear accumulation of cyclin D1 and epithelial cell proliferation. Thus, IGFs mediate mitogenic action of estrogen in the uterus during the reproductive cycle (Nayak and Giudice, 2003).
During early pregnancy, Igf1 mRNAs are observed in stromal cells of mouse uterus at days 4–6 of gestation. While the precise role of IGF1 during early pregnancy remains unclear, studies have shown that supplementation of the culture media with physiological concentration of IGF1 during IVF significantly increased blastocyst formation. Further, when extravillous trophoblast cells (EVT) were cultured in the presence of IGF1, it induced migration of EVT cells during the implantation process. Insulin-like growth factor binding proteins (IGFBPs) modulate the mitogenic and metabolic effects of IGFs, which play an important role in cell growth, metabolism and embryonic development during early pregnancy (Singh et al., 2011). In mice, IGFBP-1 is detected in uterine epithelial cells and IGFBP-4 is the predominant IGFBP in stromal cells during the periimplantation phase. It has also been reported that IGFBP3 inhibits IGF1-induced DNA synthesis in the mouse endometrial stromal cells (Nayak and Giudice, 2003). IGFBPs including IGFBP1, IGFBP2, IGFBP3, and IGFBP4 are also expressed by human endometrial stromal cells upon differentiation (Giudice et al., 1993). As pregnancy progresses, IGFs and IGFBPs continue to play an important role in formation of the placenta. Inadequate production of IGFs or IGFBPs causes abnormal placentation (Davila et al., 2015; Nayak and Giudice, 2003).
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Insulin-like growth factors (IGFs)
IGFs and their receptors are expressed in rodent and human fetal lung (Batchelor et al., 1995; Lallemand et al., 1995; Maitre et al., 1995; Retsch-Bogart et al., 1996; Schuller et al., 1995). Null mutant mice for the cognate type 1 IGF receptor (Igf1r) gene die at birth with respiratory failure and growth deficiency (45% of normal birth weight). Dwarfism is further exacerbated (70% of size reduction) in either Igf1 or Igf2 double null mutants or in Igf1r and Igf2 double null mutants. There does not appear to be a gross defect in branching morphogenesis per se; the lungs merely appear hypoplastic (Liu et al., 1993). IGF signaling may play a role in facilitating other peptide growth factor pathways during lung morphogenesis, e.g., IGF1R signaling is required for both mitogenic and transforming activities of EGFR (Coppola et al., 1994). Igf1-deficient mice have reduced airspaces, which are exacerbated in mice with additional leukemia inhibitory factor (Lif) deletion (featuring abnormal epithelium and decreased Sp3, Nkx2.1, and Sp-B expression) (Pichel et al., 2003). IGF1 is also trophic for fetal lung endothelial cells: in human fetal lung explants, IGF-IR inactivation results in endothelial cell loss, attenuates time-dependent increase in budding of distal airway, and increases mesenchymal cell apoptosis (Han et al., 2003).
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Growth Factors
Insulin-Like Growth Factors (IGFs)
Among growth factors, insulin-like growth factors (IGFs) play a pivotal role in stimulating endometrial proliferation. Studies using mice lacking IGF1 revealed that in the absence of this growth factor, the uteri are hypotrophic. Further studies revealed a dramatic upregulation of IGF1 followed by phosphorylation of insulin-like growth factor 1 receptor (IGF1R) expressed in the uterine epithelium in response to treatment with estrogen. Activation of IGF1 signaling leads to nuclear accumulation of cyclin D1 and epithelial cell proliferation. Thus, IGFs mediate mitogenic action of estrogen in the uterus during the reproductive cycle (Nayak and Giudice, 2003).
During early pregnancy, Igf1 mRNAs are observed in stromal cells of mouse uterus at days 4–6 of gestation. While the precise role of IGF1 during early pregnancy remains unclear, studies have shown that supplementation of the culture media with physiological concentration of IGF1 during IVF significantly increased blastocyst formation. Further, when extravillous trophoblast cells (EVT) were cultured in the presence of IGF1, it induced migration of EVT cells during the implantation process. Insulin-like growth factor binding proteins (IGFBPs) modulate the mitogenic and metabolic effects of IGFs, which play an important role in cell growth, metabolism and embryonic development during early pregnancy (Singh et al., 2011). In mice, IGFBP-1 is detected in uterine epithelial cells and IGFBP-4 is the predominant IGFBP in stromal cells during the periimplantation phase. It has also been reported that IGFBP3 inhibits IGF1-induced DNA synthesis in the mouse endometrial stromal cells (Nayak and Giudice, 2003). IGFBPs including IGFBP1, IGFBP2, IGFBP3, and IGFBP4 are also expressed by human endometrial stromal cells upon differentiation (Giudice et al., 1993). As pregnancy progresses, IGFs and IGFBPs continue to play an important role in formation of the placenta. Inadequate production of IGFs or IGFBPs causes abnormal placentation (Davila et al., 2015; Nayak and Giudice, 2003).
Epidermal Growth Factor (EGF) Family
The EGF family of growth factors includes EGF, TGF-α, HB-EGF, amphiregulin, β-cellulin, epiregulin, and neuregulin. Many of these members are expressed in response to steroid hormones in rodent and human endometrium during the reproductive cycle and pregnancy. The EGF-like growth factors interact with receptor subtypes that belong to an ErbB gene family of tyrosine kinase receptors: ErbB1 (EGFR), ErbB2, ErbB3, and ErbB4, which are known to be expressed in the uterine stromal cells. These receptors are structurally similar but differ in their ligand specificity and kinase activity. The expressions of EGF receptors are also regulated by steroid hormones. Studies have shown that during early pregnancy in mice, progesterone induces secretion of Indian hedgehog (IHH) by the uterine epithelial cells, which interact with their transmembrane Patched receptors (PTC) on the stromal cells to induce EGFR (Franco et al., 2010). Microarray analysis identified additional members of the EGF receptor family that are regulated by IHH, including ErbB2/Her2, ErbB3/Her3, and ErbB4/Her4 (Franco et al., 2010). In vitro studies show that epithelial EGF via stromal EGFR induces stromal cell proliferation. Administration of steroid hormones, estrogen and progesterone, along with EGF, TGF-alpha increased the percentage of BrdU-labeled stromal cells. The stimulatory effect of EGF, TGF-alpha and steroid hormones on DNA replication in the uterine stromal cells was repressed by RG-13022, an inhibitor of the EGF receptor tyrosine kinase, suggesting that EGF–EGFR signaling is a critical driver of stromal cell proliferation and differentiation. Consistent with these observations, it was found that mice lacking Egfr expression are severely subfertile. Pregnancy demise occurred shortly after embryo implantation due to defects in stromal cell proliferation and differentiation.
HB-EGF is a prominent growth factor of uterine receptivity to embryo implantation in both mice and humans. In mice, the soluble and the transmembrane form of HB-EGF are expressed exclusively at the implantation site prior to embryo attachment (Lim and Dey, 2009). Interestingly, the soluble form of HB-EGF increases the rate of human blastocyst hatching in vitro. Blastocysts from mice and human adhere to the epithelial cells expressing HB-EGF (Lim and Dey, 2009). Conditional ablation of HB-EGF expression in mouse uterine tissue markedly reduces the rate of implantation. Other growth factors including amphiregulin, betacellulin, epiregulin, neuregulin are expressed at the time of embryo implantation. However, due to their overlapping expression patterns around the implanting blastocyst at the time of attachment, mice with targeted disruptions of these growth factors do not exhibit implantation defects (Lim and Dey, 2009).
Fibroblast Growth Factors (FGFs)
Recent studies have shown that a subset of FGF family members including Fgf-1, -10, -18, and -21, are expressed by the stromal cells while the FGF receptors (FGFR) are expressed in the epithelium of rodent uteri (Li et al., 2011). Estrogen-mediated signaling by FGF–FGFR stimulates epithelial proliferation in the uterus. The FGFs via FGF receptors activate the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) and/or PI3 kinase pathway to induce expression of cyclin D1. Cyclin D1 is required for progression of cell cycle during uterine epithelial proliferation. Progesterone mediated suppression of the FGFR–ERK1/2 pathway in uterine epithelia causes the epithelial cells to exit from the cell cycle and become “receptive” for embryo implantation (Li et al., 2011). Ablation of FGFR2 in the adult uterus render the female mice initially subfertile and later infertile with increasing parity (Filant et al., 2014).
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4.1 Insulin and insulin-like growth factor
High circulating levels of insulin and IFG-1 are typical in certain kinds of cancers. In cancerous cells, these growth factors act as a mitogen promoting cell proliferation [92,93]. Additionally, the receptors for insulin and IGF1 are overexpressed in many cancers. Insulin and IGF1 bind to and activate these receptors. These receptors then activate substrates and pathways like MAPK, JAK-STAT, PI3K-Akt, and Hh leading to cell proliferation and inhibition of apoptosis [94,95]. Experiments have proved that when there is a decrease in the insulin and insulin receptor (IR) levels in mouse cancer cells, there is a significant reduction in tumor growth [96]. Additionally, inhibiting the IGF receptors showed increased sensitivity towards chemotherapeutic drugs. It underlines the importance of insulin or IGF1 and its receptors as treatment targets [97,98].
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2 The insulin-like growth factor (IGF) family
2.1 Insulin and IGF ligands
The IGF family of proteins includes three ligands: IGF1, IGF2, and insulin. All three ligands are derived from unique genes on chromosomes 12 (IGF1) and 11 (IGF2 and INS). Both IGF1 and IGF2 are primarily synthesized in the liver, however, they are also produced by several other tissues and can act in an endocrine, autocrine, or paracrine manner (Livingstone & Borai, 2014; Yakar et al., 1999). While hepatic IGF1 is produced in response to pituitary-derived growth hormone (GH) and changes with age, circulating levels of both IGF1 and IGF2 can be affected equally by hormones, genetic factors, and lifestyle factors (Frystyk, Skjaerbaek, Dinesen, & Orskov, 1994; Harrela et al., 1996; Miller, Schalch, & Draznin, 1981; Schwander, Hauri, Zapf, & Froesch, 1983). Insulin expression is regulated by many factors, however, glucose is the most important as it has been shown to play a role in insulin transcription, translation, and secretion from pancreatic β-cells to act in an endocrine fashion (Giddings, Chirgwin, & Permutt, 1982; Kulkarni et al., 2011; Layden, Durai, & Lowe, 2010; Poitout et al., 2006).
IGF1 and IGF2 are single chain polypeptides. After synthesis, they are processed in the endoplasmic reticulum where the E-peptide is cleaved, leaving the mature form containing A and B domains. Insulin is first synthesized as a single polypeptide (preproinsulin) in β-cells in the pancreas and is processed into proinsulin in the endoplasmic reticulum. However, unlike the IGF ligands, insulin is then processed into three peptides—the A and B chain peptides, which are covalently linked via two disulfide bonds and form the mature form of insulin, and the C-peptide. As indicated by their names, insulin and IGFs have substantial homology. After processing, IGF1 and IGF2 share about 70% homology in their amino acid sequence and have about 50% homology with the A and B chains in mature insulin (Bach et al., 1993). Further, the 3D structures of both IGF1 and IGF2 closely resemble that of proinsulin (Blundell, Bedarkar, Rinderknecht, & Humbel, 1978). Despite this close homology, the ligands have substantially different affinities for each of the receptors in the IGF family (discussed below).
2.2 IGF binding proteins
Though insulin is found only in a “free” state in circulation, only about 0.4% of IGF1 and 0.2% of IGF2 exists in an unbound state (Frystyk et al., 1994). Instead, IGFs in extracellular fluids are primarily found bound to six structurally related binding proteins, IGFBP-1 through IGFBP-6, which bind IGFs with equal or higher affinity to the IGF receptors, indicating that this binding is an important regulator of IGF signaling (Sitar, Popowicz, Siwanowicz, Huber, & Holak, 2006). In a free state, both insulin and IGFs have a half-life of about 10 min; however, when IGFs are bound to IGFBPs this time is increased to between 25 min and 15 h, depending on the IGFBP complex (Guler, Zapf, Schmid, & Froesch, 1989). IGFBPs share about 50% of their amino acid sequence and contain three distinct domains: an N-terminal domain, a cysteine-rich C-terminal domain, and a central linker domain. The N- and C-terminal domains are highly conserved among family members and facilitate IGF binding. The central linker domain is less conserved and is the site of the majority of the post-translational modifications found on IGFBPs (Baxter, 2000). All six members of the family have high affinity for IGF1 and IGF2, with most Kd values in the 10− 10 to 10− 11 M range (Baxter, 2000). IGFBPs are synthesized in a number of different cell types and their genes, which are spread across four chromosomes, are regulated independently.
The gene encoding IGFBP-1 is found on chromosome 7 and its expression is rapidly inhibited by insulin via suppression of transcription (Chahal et al., 2008). IGFBP-1 only binds a small fraction of circulating IGF1, however, this binding reduces bioavailability of IGF1 thereby inhibiting its activity (Brismar, Fernqvist-Forbes, Wahren, & Hall, 1994). Additionally, IGFBP-1 contains an arginine-glycine-aspartate (RGD) domain, which was found to interact with integrins, a family of cell adhesion receptors involved in cell-cell and cell-extracellular matrix interactions (Jones, Gockerman, Busby, Wright, & Clemmons, 1993). The IGFBP2 gene is located on chromosome 2 and, similar to IGFBP-1, it contains an RGD motif (Jones, Doerr, & Clemmons, 1995). IGFBP-2 protein expression in human plasma inversely correlates with fasting insulin levels and body mass index (BMI), indicating it could be used as an early marker of insulin resistance (Blum et al., 1993; Ko et al., 2012). IGFBP-3, whose gene is also found on chromosome 2, is the most abundant family member. IGFBP-3 does not contain an RGD motif, however, it does contain a basic heparin-binding motif in its C-terminus that also allows interaction with the extracellular matrix (ECM) (Fowlkes, Thrailkill, George-Nascimento, Rosenberg, & Serra, 1997). While all IGFBPs can form binary complexes with IGFs, the majority of circulating IGFs (approximately 75%–80%) form a ternary complex with IGFBP-3 and acid-labile subunit (ALS) (Leong, Baxter, Camerato, Dai, & Wood, 1992). These 150-kDa complexes are highly stable with a half-life of 12–15 h, however, they are unable to cross capillary endothelium (Guler et al., 1989; Lewitt, Saunders, Phuyal, & Baxter, 1994). Similar to IGF1, IGFBP-3 is also produced in the liver in response to GH, likely to ensure there are sufficient levels to bind and stabilize hepatically-derived IGF1 (Blum et al., 1993). IGFBP4 is found on chromosome 17, though not much is known about its regulation. Its protein product binds to IGF1 and IGF2 with similar affinities, however, unlike other IGFBPs, there is no evidence that IGFBP-4 is able to tether to cell surfaces as it lacks both RGD and heparin-binding motifs (Zhou, Diehl, Hoeflich, Lahm, & Wolf, 2003). IGFBP5 is found on chromosome 2, and its expression is regulated by glucocorticoids. IGFBP-5 is the most evolutionarily conserved binding protein and, similar to IGFBP-3, it has a heparin-binding motif and can form ternary complexes with IGFs and ALS though at much lower frequency (Andress, 1995; Twigg & Baxter, 1998). IGFBP-6 has the highest affinity for IGF2 of all the IGFBPs and also contains a heparin-binding motif (Bach et al., 1993; Fowlkes et al., 1997). Its gene resides on chromosome 12 and not much is known about the regulation of its expression.
IGFs are released from IGFBPs through methods that reduce their mutual affinity such as by binding of IGFBPS to molecules in the ECM, phosphorylation of IGFBPs, or following proteolytic cleavage of the IGFBP central linker domain by one of several proteases including pregnancy-associated plasma protein A (PAPP-A) and prostate specific antigen (PSA) (reviewed in Bunn & Fowlkes, 2003). The resulting C-terminal and N-terminal domains have substantially lower affinity for IGFs compared to the IGF receptors, but these peptides are still able to partially inhibit IGF activity (Payet, Wang, Baxter, & Firth, 2003). IGFBPs are protected from proteolytic cleavage via post-translational modifications in their linker domain (Coverley, Martin, & Baxter, 2000; Gibson, Aplin, White, & Westwood, 2001; Neumann, Marinaro, & Bach, 1998). Though IGFBPs are typically thought of as inhibitory of IGF actions, their ability to form complexes with IGFs and accumulate in the extracellular space via interactions between the heparin binding or RGD domains and the ECM allows them to act as a pericellular reservoir of IGFs, which can be released via activation of IGFBP-targeting proteases. In this way, IGFBPs can, in fact, promote IGF action by stabilizing the ligands and allowing them to be released in close proximity to their receptors, through which they exert their cellular effects.
2.3 The IGF family of receptors
IGF1, IGF2, and insulin bind to and elicit their effects through the cell surface transmembrane receptors, IGF1R, IGF2R, and insulin receptor (IR) (Fig. 1). IGF1R is found on chromosome 15 and its expression is regulated by several growth factors including GH, thyroxine, platelet-derived growth factor, and fibroblast growth factor. The mature receptor is comprised of two dimerized hemi-receptors, each made of an extracellular α-subunit and a membrane spanning β-subunit (De Meyts et al., 1994). Each α- and β-subunit are encoded by a single gene and are synthesized as a single polypeptide, known as a preproreceptor, which is processed into a proreceptor in the endoplasmic reticulum. Additional processing includes addition of a disulfide bond between the α- and β-subunits, dimerization of two proreceptors via disulfide bonds in their α-subunits, and proteolytic cleavage in order to create a mature α2β2 tetrameric receptor. IGF1R has two splice isoforms differing by three nucleotides that ultimately code for either an Arg or Thr-Gly in the extracellular portion of the β-subunit of the receptor (Condorelli, Bueno, & Smith, 1994; Tobin, Yee, Brunner, & Rotwein, 1990).
Fig. 1. Insulin and IGF system components. Components of the IGF system are discussed extensively in the text. Briefly, the IGF system is comprised of IR and IGF1R homo- and hetero-dimers which are stimulated via binding of their ligands, insulin, IGF1, and IGF2. Each ligand has differing affinities for each of the receptors—solid lines denote high affinity interactions while dashed lines denote low affinity interactions. IGF1 and IGF2 are both primarily found in circulation bound to IGF binding proteins (IGFBP). IGFs are released from IGFBPs upon proteolytic cleavage by an IGFBP protease.Adapted from Sachdev, D. & Yee, D. (2007). Disrupting insulin-like growth factor signaling as a potential cancer therapy. Molecular Cancer Therapeutics, 6(1), 1–12.
IGF2R, also called the mannose 6-phosphate receptor, is found on chromosome 6 in humans and is structurally and functionally unrelated to IGF1R and IR. Comprised of an N-terminal extracellular domain, a single membrane-spanning region, and a small cytoplasmic tail, IGF2R lacks the intracellular tyrosine kinase activity of the other two receptors in this family. It does, however, play a role in many IGF-independent biological processes including trafficking of lysosomal enzymes (Ghosh, Dahms, & Kornfeld, 2003). IGF2R expression is ubiquitous across human tissues and the receptor is also found in a soluble form in circulation (Lobel, Dahms, & Kornfeld, 1988; Oshima, Nolan, Kyle, Grubb, & Sly, 1988). In regard to IGF signaling, IGF2R predominantly acts as a decoy receptor for IGF2, as binding of IGF2 to IGF2R leads to its endocytosis and lysosomal degradation without the activation of signaling cascades associated with IGF1R and IR activation (Kornfeld, 1992).
InsR, the gene encoding IR, is located on chromosome 19. Similar to IGF1R, a mature IR is composed of two α-subunits and β-subunits, which are processed and dimerized in the endoplasmic reticulum (Knutson, 1991). Two splice variants of IR exist—full length IR-B and the short form IR-A, which lacks the 36 base pair exon 11 and is primarily expressed in fetal tissues (Frasca et al., 1999). The presence of the 12 amino acid domain encoded by exon 11 in the C-terminus of the α-subunit decreases insulin binding affinity by two to threefold, and reduces receptor internalization and downregulation (Yamaguchi et al., 1991).
The existence of these three unique receptors for IGF1, IGF2, and insulin was originally suggested in 1982, however, the relationship among these receptors has since been found to be rather complex (Sara et al., 1982). IGF1R and IR share a high degree of homology with 84% overlapping amino acid sequence in the tyrosine kinase domain, 45%–65% in the ligand-binding domain, 100% in the ATP binding domain, and over 50% in overall sequence. IGF1R and IR also share structural similarities. Both receptors have six domains in their extracellular regions—L1, CR, L2, Fn1, Fn2, and Fn3 domains—followed by a transmembrane region, an intracellular juxtamembrane region, a tyrosine kinase domain, and a C-terminal tail (De Meyts & Whittaker, 2002; Ullrich et al., 1985). Further, IGF1R and both IR variants can form functional hybrid receptors in all tissues in which the receptors are expressed (Bailyes et al., 1997; Entingh-Pearsall & Kahn, 2004; Moxham, Duronio, & Jacobs, 1989; Valensise et al., 1996). IGF2R, however, is not able to participate in these heterodimers.
Each of the insulin and IGF ligands has vastly different binding affinities for IGF1R, IR, and hybrid receptors (Fig. 1). IGF1 has greater affinity for IGF1R compared to the hybrid receptor, and almost no affinity for IR (Slaaby et al., 2006). Similarly, insulin binds to IR with far higher affinity than the hybrid receptor and has very low affinity for IGF1R (Soos, Field, & Siddle, 1993). IGF2 has equal affinity for IGF1R and IGF2R, and can also bind the IR-A/IGF1R hybrid receptor and IR-A, however, it has lower affinity for IR-B and IR-B/IGF1R hybrid receptors.
In the absence of ligand, IGF1R, IR, and hybrid receptors on the cell surface are held in an auto-inhibitory inverted “v” conformation via reciprocal interaction between the L2-Fn1 domain pairs from opposing α-subunits (Xu et al., 2018). In this state the intracellular components of the β-subunits are spatially separated preventing autophosphorylation. Binding of one molecule of ligand induces an asymmetrical conformational change that both reduces affinity for ligand in the second ligand binding pocket and induces a shift in the intracellular domain such that the kinase domains in the β-subunits come in close enough proximity to transphosphorylate tyrosine residues in the kinase domains, leading to intracellular signaling (Kavran et al., 2014; Pang & Shafer, 1984; Ward, Menting, & Lawrence, 2013).
2.4 Signaling
Binding of ligand to IGF1R and IR leads to autophosphorylation on tyrosine residues Y1131, Y1135, and Y1136 on IGF1R or Y1158, Y1162, and Y1163 on IR in their respective kinase domains, followed by phosphorylation of tyrosine residues in the juxtamembrane region (Fig. 2). These residues allow subsequent docking and phosphorylation of adaptor molecules such as insulin receptor substrate (IRS)-1, IRS-2, and SHC (Wei, Hubbard, Hendrickson, & Ellis, 1995). Additional residues allow for alternate adaptor interactions. The downstream consequences of activation of these adaptors have been well characterized. In normal tissues, IRS-1 and IRS-2 are ubiquitously expressed and are critical mediators of insulin and IGF-dependent mitogenesis and metabolic regulation (Bruning, Winnay, Cheatham, & Kahn, 1997; White, 2002; Yamauchi et al., 1996). It is important to note that different normal tissues use these signals in different ways. In the liver, activation of this pathway leads to activation of glycogen storage (Clemmons, 2004). In epithelial cells, however, phosphorylation of IRS-1 leads to activation of the PI3K/Akt/mTOR signaling cascade, ultimately promoting proliferation and pro-survival pathways (Jackson, White, & Yee, 1998). IRS-2 also leads to signaling through PI3K, however this signaling leads to alterations in cell adhesion and motility (Jackson, Zhang, Yoneda, & Yee, 2001). Activation of SHC promotes activation of proliferation via the Ras/Raf/MAPK signaling cascade. While these pathways downstream of IGF and insulin receptors are essential during both prenatal and postnatal growth, aberrant activation of these pathways has also been strongly associated with cancer development and prognosis (Pollak, 2012).
Fig. 2. Downstream pathways activated by insulin and IGF receptors. Receptor activation by insulin and IGF ligands primarily activates two major pathways—Akt and Ras/ERK. Actions of these downstream mediators induce numerous responses important in normal tissue and cancer including proliferation, survival, metabolic changes, protein synthesis, and gene transcription. IGF system-targeting methods include ligand-neutralizing antibodies, IGF1R targeting antibodies, and tyrosine kinase inhibitors (TKIs) which all target important nodes to disrupt the system.Adapted from Sachdev, D. & Yee, D. (2007). Disrupting insulin-like growth factor signaling as a potential cancer therapy. Molecular Cancer Therapeutics, 6(1), 1–12.
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Growth Hormone – Insulin-Like Growth Factor
The secretion of growth hormone (GH) from the anterior pituitary increases significantly during puberty. Like the gonadotropins, GH is secreted in pulsatile fashion during puberty; the amplitude of the pulse increases during sleep.8,9 The growth-promoting effects of GH during puberty affect many tissues, including bone growth and development, body composition, and metabolic substrates. GH stimulates IGF-1 (insulin-like growth factor-1) production in a variety of tissues, especially in the liver (the main source of circulating IGF-1) as well as in the ovaries. The simultaneous increase in GH and IGF-1 concentrations suggests regulatory interactions in the secretion and action of the two hormones.8
The IGF axis includes growth mediators, receptors, and binding proteins associated with numerous biological processes. At puberty, the circulating IGF-1 concentration is 2–3 times greater than in adulthood and increases with pubertal status. In addition to effects on substrate metabolism, IGF-1 acts on cell growth and multiplication, independently promoting pubertal growth. Thus, increases in IGF-1 affect many physiological and metabolic functions that influence growth and development during adolescence.3,8
Growth hormone secretion is regulated by hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin.10 Negative feedback for GH is mediated by its own secretion, and by the direct action of IGF-1 on pituitary and hypothalamic GHRH and somatostatin neurons.8,10 Moreover, the action of hormones of the GH-IGF1 axis is greatly influenced by estrogens and androgens.2,9 In addition, the generation and activity of IGF-1 is insulin-dependent, and insulin is an anabolic and growth promoting hormone.
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Insulin-Like Growth Factor System
It is clear that the ‘insulin-like growth factor (IGF) system’ plays a fundamental role in the growth and selection of follicles, as well as luteal development in most of the domestic species (Webb et al. 2002, Mazerbourg et al. 2003). It is likely that the IGF system integrates the metabolic status of the animal with reproductive performance (Lucy 2008, Hernandez-Medrano et al. 2012, Wathes 2012). The system comprises a number of different, but related, elements. They are: (1) two ligands, IGF1 and IGF2; (2) type 1 and type 2 IGF receptors; and (3) six principal IGF-binding proteins (IGFBPs), which have high but varying affinities for binding both IGF1 and IGF2. The predominant source of IGF1 is from the circulation, with its production by the liver increased by growth hormone (GH), whereas IGF2 is more locally produced in the follicle and CL (Lucy 2008). The circulatory levels of IGF1 parallel the energy status of that animal in several species; for example, plasma IGF1 levels decline during the period of negative energy balance postpartum in dairy cows (Lucy 2008, Wathes 2012). The principal signalling receptor is the IGF type 1 receptor, which is abundantly expressed throughout the ovary and uterus. The IGFBPs are ubiquitous in all biological fluids, including follicular fluid; however, in blood the most abundant is IGFBP3. The bioavailability of IGF1 and IGF2 is reduced when they are bound to their binding proteins, and classically, it was believed that IGFBP inhibited the action of IGFs. However, there is good evidence that the IGFBPs can potentiate IGF activity by increasing their half-life and maintaining the local tissue IGF level (Mazerbourg et al. 2003). In addition, there is also a protease that degrades IGFBPs in the follicle, called pregnancy-associated plasma protein (PAPP)-A. The action of PAPP-A on IGFBPs is to release and enable IGF1 and IGF2 to be biologically active. How does the insulin-like growth factor system function? IGFs stimulate follicular growth by stimulating granulosa cell proliferation, as well as the emergence of a dominant follicle, by sensitising follicular granulosa cells to the effects of FSH and LH. In the latter stages of follicular development, IGF1 is more involved with follicular maturation and differentiation (Mazerbourg et al. 2003). Both IGF1 and IGF2 increase oestradiol production by the granulosa cells (Mazerbourg et al. 2003). The intrafollicular levels of several IGFBPs increase during follicular atresia, and they have been proposed as markers of atretic follicles. PAPP-A has been identified in bovine, equine, ovine and porcine preovulatory follicles, concomitant with decreased IGFBP levels in preovulatory follicles (Mazerbourg et al. 2003). In the CL, IGF1 is known to stimulate progesterone by upregulating key steroidogenic proteins and has been proposed to stimulate the intense neovascularisation after ovulation (Webb et al. 2002).
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The Insulin-Like Growth Factor-1 Receptor
The growth-promoting effects of IGF-1 are mediated by IGR1Rs. IGF1R αβ subunits are encoded by a single gene.448 Like the insulin receptor, an αβ half-receptor precursor is produced that then joins with a half-receptor precursor that may be encoded from the other allele to form a complete heterotetrameric IGF1R.448 The IGF1R has 100-fold less affinity for insulin than for IGF1.477
Patients who are heterozygous for a ring chromosome 15, resulting in deletion of the IGF1R gene, present with intrauterine growth retardation and postnatal growth failure accompanied by delayed bone age, mental retardation, cardiac abnormalities, cryptorchidism, and dysmorphic features that include microcephaly, triangular face, frontal bossing, hypertelorism, and brachydactyly.478,479 Similarly, IUGR and postnatal growth failure are commonly found in patients heterozygous for deletion of distal 15q that results in deletion of the IGF1R gene. Patients with deletion of distal 15q often have microcephaly, triangular facies, hypertelorism, high-arched palate, micrognathia, cystic kidneys, and lung hypoplasia or dysplasia.477,480–482 However, the ring chromosome and deleted area of distal 15q may also be missing other genes—and it is unknown to what extent absence of the IGF1R gene contributes to the phenotype found in these patients.477,479
It has been suggested African Efe Pygmies are short due to resistance to IGF1.477 T-cell lines established from Efe Pygmies have decreased IGF1R gene expression, cell surface expression, receptor autophosphorylation, and intracellular signaling when compared with T-cell lines established from American controls.477 However, no IGF1R gene mutation has been identified in Efe Pygmies that can account for these findings.477
In addition to defective INSR function, some patients with leprechaunism and Rabson-Mendenhall syndrome are resistant to the glucose lowering or growth promotion of IGF1 and have abnormal IGF1R function—resulting in decreased ligand binding or altered intracellular signaling.477,483–487 No deleterious IGF1R gene mutation has been identified in patients with these syndromes, and many patients with leprechaunism and Rabson-Mendenhall syndrome have normally functioning IGF1Rs and no evidence of IGF1 resistance.477,488
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URL: https://www.sciencedirect.com/science/article/pii/B9781416040903500077