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At least 19 recordsLinked to original sources

PubMed1996

Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds.

The cation-dependent and cation-independent mannose 6-phosphate receptors (CD- and CI-MPRs) bind the phosphomannosyl recognition marker of lysosomal hydrolases, but in mammals the latter also interacts with insulin-like growth factor II (IGF-II). While IGF signaling is mediated by the type 1 IGF receptor (IGF1R), the type 2 receptor (IGF2R/CI-MPR) serves IGF-II turnover. Mouse mutants inheriting maternally a targeted disruption of the imprinted Igf2r gene, which is normally expressed only from the maternal allele, have increased serum and tissue levels of IGF-II and exhibit overgrowth (135% of normal birthweight) and generalized organomegaly, kinky tail, postaxial polydactyly, heart abnormalities, and edema. These mutants usually die perinatally, but a small minority can survive depending on genetic background and can occasionally reproduce, except for some females characterized by an imperforate vagina and hydrometrocolpos. Consistent with the hypothesis that lethality in the absence of IGF2R-mediated turnover is caused by excess of IGF-II overstimulating IGF1R, Igf2r mutants are completely rescued when they carry a second mutation eliminating either IGF-II or IGF1R. Normal embryonic development of the Igf1r/Igf2r double mutants, which differ from wild-type siblings only in the pattern of postnatal growth, appears to occur by signaling of IGF-II, being in excess, through a genetically identified unknown receptor, since triple mutants lacking IGF1R, IGF2R, and IGF-II are nonviable dwarfs (30% of normal size). In contrast with the Igf2r/Igf2 double mutants, mice lacking IGF2R/CI-MPR and CD-MPR survive in an IGF-II null background at a very low frequency and only for a few postnatal weeks, indicating that the mannose 6-phosphate-mediated lysosomal enzyme trafficking is essential for viability.

Animals↗

PubMed1994

Insulin-like growth factor-II (IGF-II), type 2 IGF receptor, and IGF-binding protein-2 gene expression in rat lung alveolar epithelial cells: relation to proliferation.

Pulmonary alveolar type 2 cells act as a reservoir of stem cells which can be induced to proliferate during periods of lung growth and repair after lung injury. Despite the importance of this process, the mechanisms that regulate type 2 cell proliferation have not been well characterized. We show in this study that insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) accumulates to high levels in culture medium of growth-arrested type 2 cells. This is associated with an increased expression of IGFBP-2 messenger RNA (mRNA). Study of the other components of the IGF system also reveals induction of IGF-II and type 2 IGF receptor mRNA during the process of type 2 cell block of proliferation. When growth-arrested cells are allowed to resume proliferation by the addition of serum, the level of expression of IGFBP-2, type 2 IGF receptor, and IGF-II rapidly decreased. Despite the similarities in the timing of induction, it is likely that these components are not necessarily linked to mediate effects through a single pathway. Indeed, we show that the addition of conditioned medium from growth-arrested cells on proliferative cells results in down-regulation of IGFBP-2 and increased expression of IGF-II and type 2 IGF receptor mRNA. Treatment of the cells with various concentrations of IGF-II affects only the level of expression of type 2 IGF receptor, whereas IGF-I and insulin appear to influence only the expression of IGFBP-2. From the results presented in this study, it can be suggested that IGFBP-2, IGF-II, and type 2 IGF receptor play an important role in the transition of lung alveolar epithelial cells in and out of the cell cycle.

Animals↗

PubMed1989

Structural analogs of human insulin-like growth factor (IGF) I with altered affinity for type 2 IGF receptors.

We have used site-directed mutagenesis of a synthetic gene for insulin-like growth factor (IGF) I to prepare three analogs in which specific residues in the A region are replaced with the corresponding residues in the A chain of insulin. The analogs are [Ile41, Glu45, Gln46, Thr49, Ser50, Ile51, Ser53, Tyr55, Gln56]IGF I (A chain mutant), in which residue 41 is changed from threonine to isoleucine and residues 42 to 56 of the A region are replaced, [Thr49, Ser50, Ile51]IGF I, and [Tyr55, Gln56]IGF I. These analogs are all equipotent to IGF I at the type 1 IGF receptor in human placental membranes, and in stimulating the incorporation of [3H]thymidine into DNA in the rat vascular smooth muscle cell line A10. However, the A chain mutant and [Thr49, Ser50, Ile51]IGF I have greater than 20-fold lower relative affinity for the type 2 IGF receptor of rat liver membranes, respectively. In contrast, [Tyr55, Gln56]IGF I has 7-fold higher affinity than IGF I for the type 2 IGF receptor. Residues 49, 50, and 51 in IGF I are Phe-Arg-Ser and are strictly conserved in IGF II. Residues 55 and 56 of IGF I and the corresponding residues in IGF II are Arg-Arg and Ala-Leu, respectively. Thus, the presence of the charged residues at these positions in IGF I appears to be responsible, in part, for the lower affinity of IGF I for the type 2 IGF receptor. In addition to the alterations in affinity for the type 2 IGF receptor, the A chain mutant has a 7-fold increase in affinity for insulin receptors, and [Thr49, Ser50, Ile51]IGF I has a 4-fold lower affinity for acid-stable human serum binding protein. These data strongly suggest that specific determinants in the A region of IGF I are important for maintaining binding to the type 2 IGF receptor, and that these determinants are different from those required for maintaining high affinity for the type 1 IGF receptor.

Amino Acid Sequence↗

PubMed1996

GH regulation of the Type 2 IGF receptor in regenerating skeletal muscle of rats.

GH enhances skeletal muscle growth, and IGF-II peptide is highly expressed during regeneration. We have therefore investigated the effect of GH administration on IGF-II binding and expression in regenerating rat skeletal muscle using the techniques of receptor autoradiography and in situ hybridisation. Notexin, a myotoxin, was injected into the right M. biceps femoris (day 0), causing affected fibres to undergo necrosis followed by rapid regeneration. Animals were administered either GH (200 micrograms/100 g body weight) or saline vehicle daily. Contralateral muscles were used as regeneration controls. GH administration during regeneration resulted in significant increases in body weight, and damaged and undamaged muscle weights (P < 0.001). IGF-II expression, which was examined in regenerating fibres, survivor fibres and undamaged fibres, varied according to tissue type (P < 0.001). Specifically, IGF-II expression in regenerating fibres was elevated relative to control and survivor fibres after day 3 (P < 0.05), with a peak on day 9 (P < 0.001). GH did not affect IGF-II message levels. 125I-IGF-II binding in regenerating muscle was examined in the same fibre types as well as in connective tissue. 125I-IGF-II binding in regenerating fibres was higher (P < 0.001) than in other tissue types on day 5. GH administration increased 125I-IGF-II binding in all damaged muscle tissues on day 5 (P < 0.001, regenerating fibres; P < 0.01, others). We believe that this shows for the first time an effect of GH on the Type 2 IGF receptor in regenerating skeletal muscle.

Animals↗

PubMed1986

Purification of the insulin-like growth factor II (IGF-II) receptor from an IGF-II-producing cell line, and generation of an antibody which both immunoprecipitates and blocks the type 2 IGF receptor.

18,54-SF cells, which secrete rat insulin-like growth factor II (rIGF-II), have abundant type 2 IGF receptors. We have purified the type 2 receptor from these cells by solubilization of crude membranes in Triton X-100, followed by chromatography on agarose-immobilized rIGF-II. A partially purified receptor preparation, obtained by chromatography of solubilized membranes over wheat germ agglutinin, was used to immunize a rabbit. The antibody generated both immunoprecipitates the type 2 receptor, and specifically inhibits IGF-II binding to a variety of rat tissues, including 18,54-SF cells, BRL-3A cells and placenta. The presence of abundant type 2 receptors on an rIGF-II-secreting cell line is consistent with an autocrine role for IGF-II in select cells.

Antibodies↗

PubMed1989

Structural characterization and immunohistochemical localization of receptors for insulin-like growth factor II in the rat pituitary gland.

Insulin-like growth factor II (IGF-II) receptors were detected, localized, and structurally characterized in rat pituitary tissue sections and cultures of dispersed pituitary cells by immunohistochemistry, and affinity labeling with gel electrophoresis. Using highly specific antisera against IGF-II receptors (type 2 IGF receptors) and somatotropin (GH), intense type 2 receptor immunoreactivity was detected in both anterior and intermediate pituitary lobes. In anterior pituitary sections and cultures, type 2 receptor immunoreactivity colocalized to most GH-immunoreactive cells (somatotropes), as well as cells which did not contain GH. Intermediate lobe immunoreactivity was uniformly distributed throughout the parenchyma. In both anterior and intermediate pituitary lobes, type 2 receptor immunoreactivity was predominately localized to the plasma membrane of labeled cells, with little or no cytoplasmic labeling. GH immunoreactivity, on the other hand, was intracellular. Affinity labeling of microsomal membranes from anterior and neurointermediate pituitary tissues with 125I-IGF-II disclosed classical 230k type 2 receptors. The magnitude of affinity cross-linking from both lobes was similar to that of rat liver, indicating pituitary tissues, like liver tissue, are rich sources of type 2 receptors. These results suggest possible roles for IGF-II and the type 2 receptor in the regulation of synthesis or secretion of pituitary trophic hormones, including GH and pro-opiomelanocortin gene products.

Animals↗

PubMed1996

Insulin-like growth factor-I and- II in combination inhibit the release of growth hormone-releasing hormone from the rat hypothalamus in vitro.

This study was designed to investigate the feedback loop between insulin-like growth factor-I (IGF-I) and IGF-II and the hypothalamic hormones growth hormone-releasing hormone (GHRH) and somatostatin (SS) using an in vitro rat hypothalamic model. IGF-I and, to lesser extent, IGF-II, both activate type 1 IGF receptors, while type 2 receptors are activated by IGF-II alone. IGF-I, IGF-II, their various specific analogues (Des[1-3]IGF-I, [Arg54/Arg55]IGF-II and [Leu27]IGF-II), insulin and the type 2 receptor antagonist beta-galactosidase were used on their own or in combination to study their effect on GHRH and SS release. Our results suggest that the simultaneous activation of type 1 and type 2 IGF receptors is needed for the negative feedback effect of IGFs on GHRH release in this in vitro system, in agreement with earlier findings in vivo. Somatostatin was not altered by any combination of peptides.

Animals↗

PubMed1995

Regulation of the insulin-like growth factor system during normal rat lung development.

Insulin-like growth factor (IGF)-I and IGF-II are small peptide growth factors that interact with a specific membrane receptor, the type 1 IGF receptor, to stimulate cellular proliferation and/or differentiation. The actions of these growth factors and their availability to their receptors are modulated by specific binding proteins, IGF binding protein (IGFBP)-1 through -6, which together with the IGFs and IGF receptors form the IGF system. We have analyzed RNA extracted from fetal (gestation day 16 [E16] through 22 [E22]) and adult (60-day-old) rat lung for expression of each component of the IGF system. IGF-I and -II RNAs are expressed throughout fetal development. IGF-I mRNA remained relatively constant in fetal and adult lung, whereas IGF-II RNA decreased in later gestation to levels below detection by Northern analyses in adult lung. Type 1 IGF receptor expression varied little through all ages studied, whereas the type 2 IGF receptor RNA displayed developmental regulation with a decline in expression with advancing age. IGFBP-1 transcripts were not detected in fetal or adult lung. IGFBP-2 RNA was expressed from E16 to E22, although its abundance decreased in late gestation and in adult lung, with the lowest levels of expression on day E22. IGFBP-3, -4, and -5 had similar profiles of RNA abundance, with fetuses at ages E21 and E22 displaying higher levels of transcript abundance as compared with those aged E17 to E20; the lowest RNA abundance was seen at E20.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Mutants of human insulin-like growth factor II with altered affinities for the type 1 and type 2 insulin-like growth factor receptor.

With the aim to produce insulin-like growth factors (IGF) with enhanced specificity for the type 1 or type 2 IGF receptors, three mutants of IGF II have been prepared and expressed in NIH-3T3 cells. IGF II mutated at Tyr27 to Leu and Glu showed a 25- and 54-fold decrease in affinity for the type 1 IGF receptor and a 3.4- and 9.2-fold decrease in affinity for the type 2 IGF receptor. IGF II mutated at Phe48 to Glu showed a 18-fold decrease in affinity for the type 2 IGF receptor and a 2.8-fold decrease in affinity for the type 1 IGF receptor. These affinities were measured in radioreceptor assays using type 1 or 2 IGF receptor overexpressing cells. Data obtained on receptor cross-linking and thymidine incorporation assays confirmed the results of the radioreceptor assays. It is concluded that mutations of Tyr27 preferentially decrease binding to the type 1 IGF receptor and of Phe48 to the type 2 IGF receptor, either by the loss of a residue involved in receptor binding or by preferentially destabilizing the region involved in receptor binding.

Amino Acid Sequence↗

PubMed1996

Inhibition of insulin like growth factor II autocrine growth of Wilms' tumor by suramin in vitro and in vivo.

Suramin was found to affect the Wilms' tumor (WT) cell line, W13, by inhibiting in vitro growth (half-maximal inhibitory dose (ID50)=11 microM), insulin like growth factor II (IGF-II) cell binding (ID50 = 10 microM) and IGF-II induced DNA synthesis (ID50 = 8 microM). In addition, suramin inhibited cross-linking of [125I]IGF-II to the type 1 IGF receptor (IGF1R) and type 2 IGF receptor (IGF2R). Disruption of IGF-II/IGF1R interaction appears to be the main mode of action of suramin since the suramin response was abolished in the presence of the IGF1R blocking antibody, alpha IR-3. When administered to athymic mice bearing W13 heterotransplants, suramin suppressed the linear tumor growth rate by 64%.

Animals↗

PubMed1988

Structural analogs of human insulin-like growth factor I with reduced affinity for serum binding proteins and the type 2 insulin-like growth factor receptor.

Four structural analogs of human insulin-like growth factor I (hIGF-I) have been prepared by site-directed mutagenesis of a synthetic IGF-I gene and subsequent expression and purification of the mutant protein from the conditioned media of transformed yeast. [Phe-1,Val1,Asn2, Gln3,His4,Ser8, His9,Glu12,Tyr15,Leu16]IGF-I (B-chain mutant), in which the first 16 amino acids of hIGF-I were replaced with the first 17 amino acids of the B-chain of insulin, has greater than 1,000-, 100-, and 2-fold reduced potency for human serum binding proteins, the rat liver type 2 IGF receptor, and the human placental type 1 IGF receptor, respectively. The B-chain mutant also has 4-fold increased affinity for the human placental insulin receptor. [Gln3,Ala4]IGF-I has 4-fold reduced affinity for human serum binding proteins, but is equipotent to hIGF-I at the types 1 and 2 IGF and insulin receptors. [Tyr15,Leu16]IGF-I has 4-fold reduced affinity for human serum binding proteins and 10-fold increased affinity for the insulin receptor. This peptide is also equipotent to hIGF-I at the types 1 and 2 IGF receptors. The peptide in which these four-point mutations are combined, [Gln3,Ala4,Tyr15,Leu16]IGF-I, has 600-fold reduced affinity for the serum binding proteins. This peptide has 10-fold increased potency for the insulin receptor, but is equipotent to hIGF-I at the types 1 and 2 IGF receptors. All four of these mutants stimulate DNA synthesis in the rat vascular smooth muscle cell line A10 with potencies reflecting their potency at the type 1 IGF receptor. These studies identify some of the domains of hIGF-I which are responsible for maintaining high affinity binding with the serum binding protein and the type 2 IGF receptor. In addition, these peptides will be useful in defining the role of the type 2 IGF receptor and serum binding proteins in the physiological actions of hIGF-I.

Amino Acid Sequence↗

PubMed1993

Coordinate gene expression during neonatal rat heart development. A possible role for the myocyte in extracellular matrix biogenesis and capillary angiogenesis.

OBJECTIVE: Neonatal heart development is a period of active extracellular matrix deposition and capillary angiogenesis which follows the cessation of ventricular myocyte proliferation. The aim was to determine whether coordinate expression of growth factors by the ventricular myocyte could function to inhibit myocyte proliferation directly as well as indirectly by paracrine stimulation of non-myocyte extracellular matrix deposition and capillary angiogenesis. METHODS: Immunohistochemistry and northern blot hybridisations were performed on ventricular samples from fetal to mature animals of the spontaneously hypertensive (SHR) and normotensive control Wistar Kyoto (WKY) strains. RESULTS: Ventricular expression of types I, III, and IV collagen genes reached their "maximum" within the first 2-3 postnatal weeks and then rapidly declined. Expression of TGF beta 3 and SPARC were found to precede and accompany the changes in extracellular matrix gene expression during this same developmental period. TGF beta 3 was immunolocalised to fetal cardiomyocytes with very limited expression in neonatal/adult non-myocytes. Associated with the neonatal expression of TGF beta variants, transcripts for the type 2 IGF receptor gradually declined over the first three postnatal weeks. Myocyte TGF beta gene expression, latent TGF beta release, and paracrine mechanisms of action could be facilitated by residual type 2 IGF receptor expression to help mediate stimulation of non-myocyte extracellular matrix synthesis and deposition. CONCLUSIONS: Expression of select growth factors, growth factor receptors, and components of the extracellular matrix appear to be highly coordinated during ventricular remodelling which occurs during neonatal heart development. A paradigm is presented which integrates the expression patterns of various myocyte derived stimuli and their postulated impact on formation of the structural components of the neonatal heart by modulation of myocyte and non-myocyte cell types.

Animals↗

PubMed1988

Evidence that type II insulin-like growth factor receptor is coupled to calcium gating system.

In competent Balb/c 3T3 cells primed with epidermal growth factor (primed competent cells), insulin-like growth factor-II (IGF-II) stimulated calcium influx in a concentration dependent manner with the ED50 of 450 pM. When receptor-bound [125I]IGF-II was cross-linked by use of disuccinimidyl suberate, a 240 K-Da protein was radiolabeled. Excess amount of unlabeled IGF-II inhibited the affinity-labeling of the 240 K-Da protein. To further examine whether IGF-II stimulates calcium influx by acting on the type II IGF receptor, we employed polyclonal antibody raised against rat type II IGF receptor, R-II-PABl. This antibody immunoprecipitated the type II IGF receptor and inhibited IGF-II binding in Balb/c 3T3 cell membrane without affecting IGF-I binding. In primed competent cells, R-II-PABl elicited an agonistic action in stimulating [3H]thymidine incorporation. Under the same condition, R-II-PABl elicited a marked stimulation of calcium influx. These results suggest that, in Balb/c 3T3 cells, 1) relatively low concentrations of IGF-II act mainly on the type II IGF receptor; 2) the type II IGF receptor is coupled to a calcium gating system; and 3) binding of a ligand to the type II IGF receptor leads to the stimulation of DNA synthesis.

Animals↗

PubMed1996

Cellular localization of messenger RNAs for insulin-like growth factors (IGFs), their receptors and binding proteins during fetal rat lung development.

To gain insight into the role of the insulin-like growth factors (IGFs) in regulating lung development, we have used in situ hybridization histochemistry (ISHH) to examine the ontogeny and sites of expression of IGF-I and IGF-II, IGF binding proteins (IGFBP-1 to IGFBP-6), and IGF cell surface receptors in fetal rat lung from 15 to 21 days of gestation. Both IGF-I and IGF-II mRNAs were expressed throughout the developmental period studied with little change in apparent abundance. IGF-I mRNA localized to mesenchymal cells, especially those surrounding airway epithelium, while IGF-II mRNA, which was somewhat more abundant, localized predominantly to epithelia. The type 1 IGF receptor, the receptor that likely mediates the actions of both IGFs, was expressed widely in virtually all cells, whereas the expression of the type 2 IGF receptor, thought to be involved in IGF internalization and degradation, was confined to the mesenchyme and medial layers of intrapulmonary vessels. As with the IGFs, there was little apparent change in the abundance of IGF receptor mRNAs through fetal development, and the type 2 IGF receptor mRNA was more abundant. The expression of IGFBPs changed significantly during lung development. IGFBP-2, -3, -4, and -5 were expressed from day 15 of gestation, but their sites of expression and ontogeny differed. IGFBP-2 mRNA expression was abundant and constant throughout gestation and was confined to proximal and distal airway epithelia. IGFBP-3 and IGFBP-5 also were expressed by proximal airway epithelia, but also exhibited significant expression in interstitial mesenchyme and in mesenchyme surrounding vessels. The abundance of both increased as gestation progressed (IGFBP-5 greater than IGFBP-3). IGFBP-4 mRNA was confined to interstitial mesenchyme and its abundance peaked at days 16 to 19 of gestation. We found no evidence for expression of either IGFBP-1 or IGFBP-6. We conclude that the expression of IGF-I, IGF-II, and the type 1 IGF receptor throughout gestation in the lung supports a role for the IGFs in lung growth and development. The complex pattern of IGFBP expression (differing sites and ontogeny of expression) suggests that the IGFBPs modulate IGF actions at specific target sites. Furthermore, because there is little change in the expression of IGFs or IGF receptor mRNAs during fetal lung development, regulation of IGFBP expression may be essential to the control of IGF actions during lung development.

Animals↗

PubMed1990

The roles of tyrosines 24, 31, and 60 in the high affinity binding of insulin-like growth factor-I to the type 1 insulin-like growth factor receptor.

A series of insulin-like growth factor I (IGF-I) structural analogs in which one or more of the three tyrosine residues were replaced with nonaromatic residues were produced and their binding properties characterized. The single point mutations, [Leu24]IGF-I, [Ala31]IGF-I, and [Leu60]IGF-I result in an 18-, 6-, or 20-fold loss in affinity, respectively, for the type 1 IGF receptor. Multiple mutations, [Ala31,Leu60]IGF-I, [Leu24, Ala31]IGF-I, [Leu24, Leu60]IGF-I, or [Leu24, Ala31, Leu60]IGF-I result in a 520-, 240-, 1200-, or greater than 1200-fold loss in affinity, respectively, at the type 1 IGF receptor. In contrast, none of the analogs display greater than a 2-fold loss in affinity for the acid-stable human serum binding proteins. At the insulin receptor, [Ala31]IGF-I and [Leu24]IGF-I are equipotent to and 5-fold less potent than IGF-I, whereas [Leu60]IGF-I and the multiple mutation analogs are inactive up to 10 microM. Analogs [Leu24]IGF-I, [Ala31]IGF-I, and [Leu24, Ala31]IGF-I are equipotent to IGF-I at the type 2 IGF receptor, whereas all analogs containing Leu60 demonstrate little measurable affinity at this receptor. Thus, Tyr24, Tyr31, and Tyr60 are involved in the high affinity binding of IGF-I to the type 1 IGF receptor, while Tyr60 is important for maintaining binding to the type 2 IGF receptor.

Amino Acid Sequence↗

PubMed1989

[Insulin-like growth factor (IGF) receptor in human fetal erythrocytes and fetal rat liver].

In order to clarify the potential role of IGF-I in fetal growth, the dynamics of IGF receptor were investigated in comparison with insulin receptor in human and rat fetuses. In humans, the serum levels of IGF-I measured by IGF-I radioimmunoassay after acid-ethanol extraction were significantly lower in fetuses than in adult controls. Conversely, serum insulin levels in fetuses were not indistinguishable from those in adults. On the other hand, specific binding of 125I-IGF-I to human fetal erythrocytes was 2.3%, which was significantly higher than that of adult women (1.6%). Insulin binding to the erythrocytes was also higher in human fetuses than in adult controls (cord: 3.8%, adult: 3.0%). By Scatchard analysis, the changes in the specific binding of IGF-I and insulin were mainly due to the changes in the binding capacity rather than those in the binding affinity. Additionally, IGF receptor on human fetal erythrocytes was recognized as type I IGF receptor, because the binding of 125I-labelled IGF-I and 125I-labelled IGF-II could be displaced by the addition of cold IGF-I, IGF-II and insulin. In rats, serum levels of IGF-I were also much lower in fetuses than in adult controls. Specific binding of 125I-IGF-I to liver microsomal membranes was 34.3% (per 400 micrograms protein) in fetal rats (D20), which was significantly higher than that of adult rats (3.2%). Scatchard analysis indicated that these changes in 125I-IGF-I binding was chiefly due to the changes in binding capacity. On the other hand, serum insulin levels increased with progress of pregnancy, and specific binding of insulin to microsomal membranes of fetal liver increased on D21 of gestation, mainly due to the increase in binding affinity rather than binding capacity. The bindings of 125I-labelled IGF-I and 125I-labelled IGF-II to fetal liver microsomal membranes were clearly displaced by cold IGF-I and IGF-II but not by excess of cold insulin, indicating that the receptor was type 2 IGF receptor. These results suggest that IGF-I possesses much more receptor in fetal tissues than in adult tissues despite its lower concentration in fetal sera. It is speculated that IGF-I may play an important role in fetal growth and development.

Adult↗

PubMed1992

A mutant of human insulin-like growth factor II (IGF II) with the processing sites of proinsulin. Expression and binding studies of processed IGF II.

A mutant of human insulin-like growth factor II (IGF II) was constructed by site-directed mutagenesis: the nucleotides coding for Ser33 and Ser39 were changed to yield Arg and Lys, respectively, thus creating two pairs of basic residues, Arg-Arg and Lys-Arg, as flanking sequences of the remaining C domain. [Arg33, Lys39]IGF II was expressed in NIH-3T3 cells as a processed two-chain peptide with a deletion of amino acid residues 37-40 and crosslinked by three disulfide bonds. This des(37-40)[Arg33]IGF II showed 3.6-fold and 7.4-fold reduced affinities to the type 1 and type 2 IGF receptor overexpressing cells, respectively, whereas the thymidine incorporation potency was the same as that of wild-type IGF II. We speculate that the discrepancy between the reduced binding to the type 1 IGF receptor and the full thymidine incorporation potency is due to the 6.1-fold reduced affinity of the expressed mutant to the co-expressed IGF binding protein 3 (IGFBP-3). The results suggest that des(37-40)[Arg33]IGF II assumes a conformation very similar to IGF II, and that the entire length of the C domain is not essential for biological activity.

3T3 Cells↗

PubMed1995

Solution structure of human insulin-like growth factor II. Relationship to receptor and binding protein interactions.

The three-dimensional structure of human insulin-like growth factor (IGF) II in aqueous solution at pH 3.1 and 300 K has been determined from nuclear magnetic resonance data and restrained molecular dynamics calculations. Structural constraints consisting of 502 NOE-derived distance constraints, 11 dihedral angle restraints, and three disulfide bridges were used as input for distance geometry calculations in DIANA and X-PLOR, followed by simulated annealing refinement and energy minimization in X-PLOR. The resulting family of 20 structures was well defined in the regions of residues 5 to 28 and 41 to 62, with an average pairwise root-mean-square deviation of 1.24 A for the backbone heavy-atoms (N, C2, C) and 1.90 A for all heavy atoms. The poorly defined regions consist of the N and C termini, part of the B-domain, and the C-domain loop. Resonances from these regions of the protein gave stronger cross peaks in two dimensional NMR spectra, consistent with significant motional averaging. The main secondary structure elements in IGF-II are alpha-helices encompassing residues 11 to 21, 42 to 49 and 53 to 59. A small anti-parallel beta-sheet is formed by residues 59 to 61 and 25 to 27, while residues 26 to 28 appear to participate in intermolecular beta-sheet formation. The structure of IGF-II in the well-defined regions is very similar to those of the corresponding regions of insulin and IGF-I. Significant differences between IGF-II and IGF-I occur near the start of the third helix, in a region known to modulate affinity for the type 2 IGF receptor, and at the C terminus. The IGF II structure is discussed in relation to its binding sites for the insulin and IGF receptors and the IGF binding proteins.

Amino Acid Sequence↗