Insulin-like Growth Factor (IGF)-binding Protein 5 Forms an Alternative Ternary Complex with IGFs and the Acid-labile Subunit

Twigg, Stephen M.; Baxter, Robert C.

doi:10.1074/jbc.273.11.6074

Cited by 172 publications

(99 citation statements)

References 57 publications

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“…The IGFALS encodes the insulin‐like growth factor‐binding protein complex, acid labile subunit protein (ALS) which forms a ternary complex with IGF‐I and IGFBP‐3 (Firth et al ., 1998; Twigg & Baxter, 1998). Like in most GWAS, our analyses cannot establish which is the causative SNP or gene of a locus.…”

Section: Discussionmentioning

confidence: 99%

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Teumer¹,

Qi²,

Nethander³

et al. 2016

Aging Cell

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SummaryThe growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.

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Section: Discussionmentioning

confidence: 99%

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Teumer¹,

Qi²,

Nethander³

et al. 2016

Aging Cell

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“…Free to total serum IGF-I levels tended to increase (P ϭ 0.066) in Igfbp5 line 3 hemizygote adults (3.60 Ϯ 0.67%; n ϭ 9) versus WT siblings (1.03 Ϯ 0.94%; n ϭ 5), thus total free IGF-I concentrations increased significantly in the transgenic mice (Tg, 4.79 Ϯ 0.63; WT, 2.05 Ϯ 0.90 ng͞ml; P Ͻ 0.05). IGFBP-5-myc was observed at molecular weights equivalent to those observed for ternary and binary complexes (9) and for free protein, indicating possible interaction with IGFs and acid-labile subunit (Fig. 12, which is published as supporting information on the PNAS web site).…”

Section: Reduced Litter Size and Increased Morbidity Correlated With mentioning

confidence: 96%

“…In mice, Igfbp5 is expressed in the embryo from early development, principally in the myotomal component of the somites and developing central nervous system (8). Postnatally, serum IGFBP-5, in common with IGFBP-3, forms a ternary complex with IGF-I or IGF-II and the acid-labile subunit (9). Igfbp5 is up-regulated in the aggressive pediatric cancer, rhabdomyosarcoma (10), in the progression of prostate cancers to androgen independence (11), and in smooth muscle-derived uterine leiomyoma (12), indicating a function in neoplasia.…”

mentioning

confidence: 99%

Insulin-like growth factor-binding protein 5 ( Igfbp5 ) compromises survival, growth, muscle development, and fertility in mice

Salih

Tripathi

Holding

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

160

123

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The insulin-like growth factors (IGFs) are essential for development; bioavailable IGF is tightly regulated by six related IGF-binding proteins (IGFBPs). Igfbp5 is the most conserved and is developmentally up-regulated in key lineages and pathologies; in vitro studies suggest that IGFBP-5 functions independently of IGF interaction. Genetic ablation of individual Igfbps has yielded limited phenotypes because of substantial compensation by remaining family members. Therefore, to reveal Igfbp5 actions in vivo, we generated lines of transgenic mice that ubiquitously overexpressed Igfbp5 from early development. Significantly increased neonatal mortality, reduced female fertility, whole-body growth inhibition, and retarded muscle development were observed in Igfbp5-overexpressing mice. The magnitude of the response in individual transgenic lines was positively correlated with Igfbp5 expression. Circulating IGFBP-5 concentrations increased a maximum of only 4-fold, total and free IGF-I concentrations increased up to 2-fold, and IGFBP-5 was detected in high Mr complexes; however, no detectable decrease in the proportion of free IGF-I was observed. Thus, despite only modest changes in IGF and IGFBP concentrations, the Igfbp5-overexpressing mice displayed a phenotype more extreme than that observed for other Igfbp genetic models. Although growth retardation was obvious prenatally, maximal inhibition occurred postnatally before the onset of growth hormone-dependent growth, regardless of Igfbp5 expression level, revealing a period of sensitivity to IGFBP-5 during this important stage of tissue programming.T he insulin-like growth factors (IGF-I and -II) are essential for growth and development (1). Six high-affinity IGF-binding proteins (IGFBP-1 to IGFBP-6; refs. 2 and 3) strictly orchestrate IGF action. Despite their considerable sequence homology, each exhibits a discrete expression pattern and possesses an individual subset of motifs, signifying that although IGFBPs have common actions, they may also have unique properties.IGFBP-5 is the most conserved of the IGFBPs (4) and has been highlighted as a focal regulatory factor during the development of several key cell lineages, e.g., myoblasts (5) and neural cells (6, 7). In mice, Igfbp5 is expressed in the embryo from early development, principally in the myotomal component of the somites and developing central nervous system (8). Postnatally, serum IGFBP-5, in common with IGFBP-3, forms a ternary complex with IGF-I or IGF-II and the acid-labile subunit (9). Igfbp5 is up-regulated in the aggressive pediatric cancer, rhabdomyosarcoma (10), in the progression of prostate cancers to androgen independence (11), and in smooth muscle-derived uterine leiomyoma (12), indicating a function in neoplasia.IGFBP-5 initially binds IGFs with high affinity, principally by an N-terminal motif (13), and inhibits IGF activity by preventing IGF interaction with the type 1 receptor. It is further subject to regulated posttranslational modifications (3) to induce conformational changes that dec...

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“…In circulation, it is present in a tertiary complex containing IGFBP5, an IGF ligand, and the acidlabile subunit. 34 This tertiary complex controls the efflux of IGFs from the vascular space and prolongs the half-lives of IGFs. IGFBP5 is also expressed in many fetal, neonatal, and adult tissues and local IGFBP5 can modulate IGF activities in an autocrine/paracrine manner 15 or can have ligand-independent action.…”

Section: Discussionmentioning

confidence: 99%

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

et al. 2013

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Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca 2 þ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca 2 þ -transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca 2 þ ] environments. BrdU pulse-labeling experiments suggest that low [Ca 2 þ ] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca 2 þ ] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca 2 þ -selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca 2 þ ]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca 2 þ ]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca 2 þ ]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca 2 þ ]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca 2 þ ]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca 2 þ ] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca 2 þ deficiency.

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Insulin-like Growth Factor (IGF)-binding Protein 5 Forms an Alternative Ternary Complex with IGFs and the Acid-labile Subunit

Cited by 172 publications

References 57 publications

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Insulin-like growth factor-binding protein 5 ( Igfbp5 ) compromises survival, growth, muscle development, and fertility in mice

Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

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