the role of insulin-like growth factor binding proteins
TRANSCRIPT
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Neuroendocrinology 2006;83:154–160 DOI: 10.1159/000095523
The Role of Insulin-Like Growth Factor Binding Proteins
Jeff Holly Claire Perks
Department of Clinical Science at North Bristol, University of Bristol, Bristol , UK
proinsulin, and thus, they acquired their present names. By that time, it had been shown that in addition to pro-duction in the liver, both IGFs were produced in most, if not all, tissues. However, the liver has been confirmed as by far the main source of the large amount of IGFs found in the circulation, and it became increasingly apparent that pituitary GH was not the only regulator but that they were also very strongly nutritionally dependent. Nutri-tion has many interacting effects upon the IGF system, including direct effects on hepatic expression and indi-rect effects via insulin and changes in hepatic GH recep-tors [2] . IGFs play a fundamental role in regulating so-matic growth according to nutritional conditions and en-suring that the development of the organism proceeds appropriately to the nutritional supply. This control sys-tem has been conserved throughout evolution from yeast through Caenorhabditis elegans, Drosophila and rodents to higher mammals. A plentiful food supply results in rapid growth and development and early acquisition of the reproductive status, so that the next generation can take advantage of the good food supply, as well as a short-er lifespan, favoured on an evolutionary basis as post-re-productive adults have served their purpose and are then just competitors for the food supply with the next gen-eration.
Both IGF-I and IGF-II have multiple actions on cells that are mediated by the same IGF-I receptor: a classical transmembrane tyrosine kinase cell surface receptor. Like the ligands, the IGF-I receptor is remarkably similar to the insulin receptor, particularly in the tyrosine kinase
Key Words Insulin-like growth factor-I � Insulin-like growth factor binding proteins � Growth hormone
Abstract Insulin-like growth factors (IGFs) are fundamental cell regu-lators with an evolutionary conserved role synchronising tis-sue growth, development and function according to meta-bolic conditions. Although structurally very similar to insulin, the IGFs act in a very different way as cell regulators. Where-as insulin is stored in a specific gland and released when needed, the IGFs are stored outside of cells with soluble binding proteins. A very complex system of six IGF binding proteins, each of which exists in various modified states and interacts with other proteins, provides a sophisticated sys-tem for conferring specificity to provide a finely tuned sys-tem for local regulation at the tissue level.
Copyright © 2006 S. Karger AG, Basel
Introduction
The insulin-like growth factors (IGF)-I and IGF-II were first described in the late 1950s as skeletal growth factors produced in the liver in response to pituitary growth hormone (GH) and which then mediated the reg-ulation of whole-body, somatic growth [1] . Eventually, when their chemical structure was characterised, it was apparent that they share close structural homology to
Published online: October 13, 2006
Jeff Holly Department of Clinical Science at North Bristol, University of Bristol Paul O’Gorman Lifeline Centre, Southmead Hospital Bristol, BS10 5NB (UK) Tel. +44 117 959 6237, Fax +44 117 959 5342, E-Mail [email protected]
© 2006 S. Karger AG, Basel 0028–3835/06/0834–0154$23.50/0
Accessible online at: www.karger.com/nen
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domain and in the shared intracellular signalling path-ways that they activate [3] . There is also an IGF-II recep-tor which is a single large transmembrane receptor that is completely unrelated to the IGF-I and insulin recep-tors. The IGF-II receptor does not appear to act as a tra-ditional signalling receptor in response to IGF binding and is thought to act mainly as a clearance receptor for IGF-II: disruption of gene expression in mice results in elevated IGF-II levels and overgrowth.
IGF Binding Proteins Determine the Modus Operandi of IGFs
Although the IGFs, their receptors and consequent in-tracellular signalling are very similar to insulin, they have evolved to function as very different communica-tion systems in mammals. Principally, the expression of insulin is restricted to the pancreas where it is stored in secretory granules within the islet � -cells from which it is secreted via the regulated pathway in response to stim-uli such as glucose, whereas the IGFs are expressed wide-ly throughout most tissues in the body. In addition, like most other peptide growth factors and cytokines, the IGFs are not stored in secretory granules within cells, but are secreted as they are produced, via the constitutive se-cretory pathway. Furthermore, when insulin is secreted from the pancreas, it enters the circulation and passes around the body until it encounters a cell receptor in a target tissue. In contrast, when the IGFs are secreted, they associate with soluble high-affinity binding proteins, the IGFBPs. It was apparent early on that all of the IGFs in the circulation were much larger in size than the actual peptides alone and that this was due to the association with proteins that specifically bound to IGFs but not to insulin [4] .
There are six high-affinity binding proteins (IGFBP-1 to IGFBP-6) that are unrelated to the cell surface recep-tors. These IGFBPs are closely related to each other struc-turally, although they are distinct gene products and they all have very distinct functional properties [5] . In terms of physiology, there is still very limited understanding of the exact role of most of the IGFBPs. The binding to these IGFBPs considerably slows the clearance of the IGFs re-sulting in the build-up of very high concentrations. In the circulation, two of the IGFBPs, IGFBP-3 and IGFBP-5, are bound to a further large glyoprotein, the acid-labile sub-unit (ALS), that is present in excess. This ternary complex slows clearance even more, such that in adult humans, the total IGF-I and IGF-II concentration in the circulation is
around 100 n M . This is approximately 1,000 times higher than insulin and most other peptide growth factors and hormones. At the cellular level, optimal regulation of the IGF-I receptor is achieved with just 1- to 2-n M concentra-tions, indicating that there is a vast excess in the circula-tion. In the tissues, IGF concentrations are around a third of that in the circulation, but this is still much higher than the concentration needed for cell regulation. Therefore, while IGFs are not stored within cells, there appears to be a large extra-cellular amount maintained in complexes with IGFBPs. With insulin, the activity throughout the body is largely determined by the rate of regulated secre-tion from the pancreas; with IGFs, the critical regulation of activity has shifted to where they are stored – outside of the cells in association with the IGFBPs. The constitu-tive cell secretion of IGFs within any tissue is just one component of the total amount of IGFs to which the cells are exposed. The IGFs are bound to the IGFBPs with higher affinity than that with which they bind to the IGF-I receptor, so most of the IGFs in the body are potentially not available for receptor activation. Therefore, activity in a tissue is not necessarily determined by the secretion rate of IGFs and not necessarily determined by total IGF concentration. It is not safe either to assume that IGF has to be released from a binding protein in solution and it is then just the soluble-free IGF that is active. There is con-siderable evidence that IGFBPs cannot only sequester IGFs away from cell receptors and restrict activity, but they can also enhance activity at the cellular level. This can occur via a variety of mechanisms including the as-sociation with the cell membrane increasing IGF concen-tration in the local vicinity of cell receptors and by pre-vention of receptor down-regulation [5] .
IGFBP Physiology
In humans, IGFBP-3 clearly acts as the main circulat-ing carrier protein, although it is also expressed exten-sively in many tissues and obviously has additional local functions. One of the proteins, IGFBP-1, is more restrict-ed in its sites of expression; the IGFBP-1 that is present in the circulation is predominantly derived from the liver where its expression is under the dynamic control of in-sulin which suppresses its production. In the circulation, IGFBP-1 levels undergo a circadian variation due to this dynamic insulin regulation [6] . This appears to provide an additional acute control to ensure that IGF activity is appropriate to nutritional conditions. When nutrition is limited, insulin levels decrease, and this results in in-
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creasing IGFBP-1 levels which then restrict IGF activity [7] . During childhood, this contributes to the controls which ensure that somatic growth is synchronised to the metabolic status. In diabetes and insulin-resistant states, the regulation of IGFBP-1 is disturbed, which could then contribute to the associated comorbidities.
IGF Availability: IGFBP Proteases
With the large quantities of latent IGFs associated with IGFBPs, bound with greater affinity than the cell receptor, it was clear that there must be mechanisms for making this IGF available for actions in the tissues. In the circu-lation, the majority of IGF is associated with IGFBP-3and the ALS. The ALS binds to a C-terminal region of IGFBP-3 that also binds to proteoglycans present on cell surfaces and in the extracellular matrix (ECM). There-fore, it is possible that proteoglycans on the surface of the capillary endothelium compete for binding to IGFBP-3 and displace the ALS generating a binary complex from the ternary complex. The binary complex would then be able to cross the endothelium and transport the IGF into the tissue. However, there is another mechanism for con-trolling delivery of IGF from the circulatory reservoir. A circulating protease that acts specifically upon IGFBP-3 has been described in many different conditions [8] . This protease results in limited cleavage of IGFBP-3; the cleaved IGFBP-3 still retains IGF in the ternary complex, but it is bound with a lower affinity. Even a small decrease in af-finity could result in a shift in the complex equilibrium with the IGF re-equilibrating to other IGFBPs that are present and which are generally not cleaved by the same protease. These other IGFBPs only form binary complex-es, and therefore, have greater ability to transport theIGFs out into target tissues. There have been many studies documenting increases in IGFBP-3 proteolysis in the cir-culation in pregnancy and many other conditions, espe-cially catabolic states [8] , where an increase in availability of an anabolic metabolic regulator could be an advantage. In humans, proteases capable of cleaving IGFBP-3 appear to be ubiquitously present both in the circulation and in extra-vascular fluids. In the normal healthy individual, there is little detectable IGFBP-3 protease activity in se-rum due to the presence of inhibitors which protect the IGFBP-3 from proteolysis. The increase in proteolysis that is observed in different conditions appears to be due to a decrease in these inhibitors, rather than an increase in levels of proteases [9] . Outside of the circulation in the tis-sues, this system appears to operate quite differently. The
protease inhibitors appear to be restrained to within the circulation, whereas the same proteases that are present in the circulation are also present in extra-vascular intersti-tial fluids. Consequently, IGFBP-3 protease activity is un-opposed and proteolysis of IGFBP-3 is more extensive in the tissues, presumably making the IGF more available for cell receptors. This system in the tissues is disturbed in inflammatory conditions, where an increase in capillary permeability enables the circulating protease inhibitors access to the extra-vascular space, and IGFBP-3 proteoly-sis is then suppressed [9] .
In addition to the IGFBP-3 protease, it has become clear that there are proteases and accompanying inhibi-tors for each of the individual IGFBPs, the most fully characterised being the pregnancy-associated plasma protein A system for cleaving IGFBP-4 [10] .
Actions of IGFBPs Independent of IGFs
It is now very well established from the work of many laboratories that in addition to all of the effects of IGFBPs that involve altering the storage, transport and delivery of IGFs and inhibiting and enhancing their cel-lular actions, each of the IGFBPs also has a separate set of actions that are independent of any interaction with IGFs. These intrinsic actions of IGFBPs are often referred to as ‘IGF-independent’ actions, because they are not depen-dent upon the binding and modulation of IGF activity. However, in many instances, these actions are not en-tirely IGF independent because the intrinsic action of the IGFBP can be modulated when an IGF is bound to the IGFBP. For example, the binding of IGFs to IGFBP-3 can block its intrinsic action on cells [11] , which appears to be due to reducing its binding to the cell surface [12] in an analogous manner to IGFBPs reducing IGF interactions with cell surface receptors. There is also evidence that the binding of IGFs similarly alters the affinity of IGFBP-5 for proteoglycans and the cell surface [13] , and it is likely that IGF binding will affect the intrinsic actions of this and other IGFBPs. As a consequence, there will be com-plex balances in vivo with IGFBPs modulating the potent growth and survival actions of the IGFs and the intrinsic actions of the IGFBP in turn being modulated by the IGFs. Intrinsic actions of IGFBPs on cell growth, surviv-al, migration and attachment have been described, and it is clear that just like the IGFs themselves, the IGFBPs are pluripotential cell regulators.
The six specific IGFBPs are structurally related to a larger group of proteins that share more limited homol-
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ogy but clearly form more distant relatives of a superfam-ily of proteins that evolved from a common ancestral gene [14] . These distant relatives include another group of proteins referred to as CCN proteins which include NOV, mac25, CTGF and CYR61. Like IGFBPs, the CCN proteins are all cysteine-rich modular proteins with many pleiotropic actions on cell functions similar to the intrin-sic actions of IGFBPs [15] . It seems likely that the IGFBPs evolved as part of this family of cell regulatory proteins and then acquired an ability to bind IGFs and modulate IGF activity which complemented their original func-tions. This is analogous to other binding proteins, for ex-ample corticosteroid-binding globulin (CBG), which evolved as part of a large family of proteinase inhibitors and subsequently acquired an ability to bind corticoste-roids. The CBG still interacts with proteinases, and al-though it no longer acts as a proteinase inhibitor, this interaction still has functional significance: CBG is cleaved by neutrophil elastase which lowers the affinity of cortisol binding and hence acts to deliver cortisol to sites of inflammation. Therefore, a protein which prob-ably evolved to control proteinase activity at sites of tissue damage acquired a further advantage in modulating the delivery of another cell regulator. It seems likely that IGFBPs evolved as intrinsic cell regulators that subse-quently acquired an ability to affect cell metabolism via binding and modulating the activity of IGFs which then complemented their original function. Many of the in-trinsic actions of IGFBPs appear to be controlling cell stress responses, and an ability to affect cell metabolism in situations of stress could clearly be an additional ad-vantage. A better understanding of the complex intrinsic actions of IGFBPs may therefore be forthcoming from comparisons with their ancestral relatives.
A clearly defined mechanism has been established for the intrinsic actions of two of the IGFBPs, IGFBP-1 and IGFBP-2. These are the only high-affinity IGFBPs to pos-sess an arginine-glycine-aspartic (RGD) motif which is a classical integrin receptor recognition sequence. The di-rect IGF-independent actions of IGFBP-1 on cell migra-tion of smooth muscle cells and trophoblasts in the pla-centa [16, 17] are mediated by interaction of this sequence with the � 5 � 1 integrin receptor [18] . Integrin binding via the RGD motif within IGFBP-1 and IGFBP-2 also results in the induction of focal adhesion kinase dephosphoryla-tion, cell detachment and subsequent apoptosis of human breast cancer cells [19, 20] .
A number of mutant IGFBPs have been produced that do not bind to IGFs but which still demonstrate the in-trinsic actions on cells, and a study using transgenic mice
generated to express a non-IGF-binding mutant IGFBP-3 has also demonstrated that the IGFBPs have intrinsic ac-tions in vivo [21] . The IGFBPs are modular proteins with conserved N- and C-terminal domains that are involved in their shared function of binding IGFs and a mid-region domain within which there is no homology and within which most of the post-translational modifications oc-cur. The intrinsic actions of IGFBPs are generally very specific for individual IGFBPs [22] , and it seems likely that the non-shared mid-region of these proteins may be responsible for these non-shared specific actions, other than the RGD integrin-binding sequences within the C-terminal domains of IGFBP-1 and IGFBP-2. Mid-region peptides from IGFBP-3 have been reported to mimic the actions of IGFBP-3 [23] and also to bind to the putative IGFBP-3 receptor [24] . In addition, phosphorylation of serines within this mid-region can negate IGF-indepen-dent actions [23] , consistent with the very specific actions of IGFBP-3 being due to an active region within the non-conserved mid-domain of the molecule and these actions being regulated by post-translational modifications.
Other than the distinct integrin interactions of IGFBP-1 and IGFBP-2, the mechanisms of the intrinsic actions of the other IGFBPs are less clear. There have been reports of putative IGFBP-3 and IGFBP-5 cell surface re-ceptors [25, 26] that could mediate their intrinsic actions. An association of IGFBP-3 with the transforming growth factor- � type V receptor [27] has also been reported. At present, all of these associations are putative ‘IGFBP re-ceptors’ and are yet to be confirmed by independent lab-oratories. In addition, links between these putative recep-tors and intracellular signalling events and consequent altered cell functions have yet to be established.
Another possible mechanism of IGFBP action was suggested when it became clear that both IGFBP-3 and IGFBP-5 possess nuclear localisation sequences [28] and can be found in the nucleus, at least in cells in culture. This raised the possibility that they may be able to di-rectly modulate transcriptional activity; indeed, it was then shown that IGFBP-3 can bind to the retinoid RXR receptor [29] . However, such potential actions via regu-lating gene transcription could not explain the very rapid cellular responses such as IGFBP-3 modulating the phos-phorylation status of signalling molecules such as mito-gen-activated protein kinase [30] and Smad2 and Smad3 [31] or the very rapid effects on cell adhesion and apop-tosis [32, 33] . The RXR heterodimerises with many other nuclear receptors, and one of the interesting prospects raised by the binding of IGFBP-3 to RXR was the poten-tial to modulate cell metabolic responses via effects on
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PPAR � -mediated actions. Although IGFBP-3 has been reported to modify insulin sensitivity of adipocytes, this does not appear to involve RXR binding [34] . Whether IGFBPs have physiological nuclear actions remains to be established.
Interactions of IGFBPs with integrin receptors could provide a further mechanism by which they could modu-late cellular responses independently of IGF-I, even for IGFBPs, which lack conventional integrin recognition se-quences. Despite not possessing a classical RGD sequence, IGFBP-3 can also modulate the localisation of focal adhe-sion kinase in breast cancer cells completely independent of IGF [35] . The IGF-independent modulation of both apoptosis and cell attachment by IGFBP-3 are blocked in the presence of a sub-apoptotic dose of a disintegrin [33] . These data suggest that IGF-independent actions of IGFBP-3 and IGFBP-5 may be mediated via as yet un-characterised interactions with integrin receptors. No specific cell surface receptors have been described for the related CCN proteins, but it is now recognised that they generally act via integrin receptors with which they inter-act through non-classical recognition sequences [36] . Similarly, although IGFBP-3 and IGFBP-5 do not possess classical integrin recognition sequences, IGFBP-3 has been reported to associate with the � 1 integrin [35, 37] , and IGFBP-3 and IGFBP-5 are know to bind with high
affinity to many known integrin ligands such as fibrin, fibrinogen [38] , fibronectin [39] , ADAM-12 [40] , plas-minogen [41] , thrombospondin and osteopontin [42] , and to caveolin-1 and the transferrin receptor [37, 43] . It is possible that these IGFBPs interact with integrin recep-tors via one of these intermediates or directly via a non-classical integrin recognition sequence.
A further interesting mode of action arises from the interaction of IGFBPs with proteinases. In addition to their susceptibility to proteolysis which control IGF avail-ability and may also free IGFBPs from IGF for intrinsic actions, it also appears that IGFBPs may regulate protease activity. It has recently been demonstrated that IGFBP-5 can activate plasminogen by interaction with tissue plas-minogen activator [44] . Activation of proteases such as plasmin could affect cell functions in a number of poten-tial ways, such as via degradation of the ECM.
Summary
All of the IGFs present in the body are effectively pres-ent in IGFBP complexes, and there is clearly a very com-plex system with six IGFBPs, each of which is present in a number of functionally distinct forms due to various post-translational modifications. Each of the IGFBPs is
Type 1receptor
Hybridreceptor
Insulinreceptor
Type 2receptor
IGFBP-1 IGFBP-2
ALS
IGFBP-4
IGFBP-6IGFBP-3
IGF-I IGF-II Insulin
Cell surfaceIGFBP
IGFBP-1protease IGFBP-3 protease
IGFBP-5protease
IGFBP-6protease
IGFBP proteaseactivator
IGFBP-5
IGFBP-2protease
PAPP-A
IGFBPreceptor
IGFBP-4protease
IGFBP-3 proteaseinhibitor
Fig. 1. Six IGFBPs provide a complex sys-tem of interacting components that pro-vides a readily available store of IGFs and a sophisticated local regulation system. PAPP-A = Pregnancy-associated plasma protein A.
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modified by specific proteases which in turn are con-trolled by specific inhibitors. The proteolysis may not only determine IGF availability but could also affect the intrinsic actions of the IGFBPs. Each of the IGFBPs inter-acts with many other proteins, particularly in the ECM and on the cell surface ( fig. 1 ). The pattern of expression of all of these interacting components varies between tis-sues, and within a tissue, varies in developmental stage and pathology. This sophisticated complexity of compo-nents for controlling IGF availability and actions pro-vides a means whereby specificity can be conferred on the system. Since their original description as cell growth factors and the realisation that they also possessed meta-bolic insulin-like activity, it subsequently became clear
that the IGFs are pluripotential cell regulators. In addi-tion to regulating growth and metabolism, they are po-tent cell survival factors and can regulate cell motility, differentiation and most, if not all, differentiated cell functions. These peptides are ubiquitously present in vast excess and can potentially regulate every cell function. The IGFBPs maintain a readily available extracellular store of IGFs and provide a mechanism for integrating IGF activity with many other regulators via a sophisti-cated interplay of multiple components which appears to provide a means of conferring specificity such that cell functions can be very finely controlled in a tissue-spe-cific manner.
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