IGFBP3

Last updated
IGFBP3
Identifiers
Aliases IGFBP3 , BP-53, IBP3, insulin like growth factor binding protein 3
External IDs OMIM: 146732; MGI: 96438; HomoloGene: 500; GeneCards: IGFBP3; OMA:IGFBP3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3486

16009

Ensembl

ENSG00000146674

ENSMUSG00000020427

UniProt

P17936

P47878

RefSeq (mRNA)

NM_001013398
NM_000598

NM_008343

RefSeq (protein)

NP_000589
NP_001013416

NP_032369

Location (UCSC) Chr 7: 45.91 – 45.92 Mb Chr 11: 7.16 – 7.16 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Insulin-like growth factor-binding protein 3, also known as IGFBP-3, is a protein that in humans is encoded by the IGFBP3 gene. IGFBP-3 is one of six IGF binding proteins (IGFBP-1 to IGFBP-6) that have highly conserved structures and bind the insulin-like growth factors IGF-1 and IGF-2 with high affinity. IGFBP-7, sometimes included in this family, shares neither the conserved structural features nor the high IGF affinity. Instead, IGFBP-7 binds IGF1R, which blocks IGF-1 and IGF-2 binding, resulting in apoptosis. [5]

Contents

Function

IGFBP-3 was first isolated, characterized, and quantitated in human plasma, in 1986. [6] [7] It has well-documented functions in the circulation, in the extracellular environment, and inside cells. It is the main IGF transport protein in the bloodstream, where it carries the growth factors predominantly in stable complexes that contain the binding protein, either IGF-1 or IGF-2, and a third protein called the acid-labile subunit or ALS.

For IGFs to reach the tissues from the bloodstream, the circulating complexes are believed to partly dissociate, possibly enhanced by limited proteolysis of IGFBP-3. The IGF-1/IGFBP-3 ratio has sometimes been used as an index of IGF bioavailability in the human circulation, but this ignores IGF-1 binding to other IGFBPs (so the ratio is affected by the concentrations of all six IGFBPs), and the fact that IGF-2, which is three times more abundant than IGF-1 in the bloodstream of adults, occupies the majority of binding sites on circulating IGFBP-3.

Within tissues, IGFBP-3 can bind IGF-1 and IGF-2 released by many cell types, and block their access to the IGF-1 receptor (IGF1R), which is activated by both IGFs. IGFBP-3 also interacts with cell-surface proteins, affecting cell signaling from outside the cell or after internalization, and also enters the cell nucleus where it binds to nuclear hormone receptors and other ligands. High levels of IGFBP-3 within tumors are associated with increased cancer severity (or worse outcome) for some cancers, but decreased severity or better outcome for others. No cases of IGFBP3 gene deletion in humans have been reported, but mice lacking the gene show near-normal growth.

Gene and protein structure

The IGFBP3 gene (or IBP3), on human chromosome 7, is organized into four protein-coding exons with a 5th exon in the 3' untranslated region. [8] It is located adjacent to the IGFBP1 gene in tail-to-tail orientation, separated by 20 kb. [9] The encoded protein includes a 27-residue signal peptide followed by the 264-residue mature protein. IGFBP-3 shares with the other five high-affinity IGFBPs and a 3-domain structure: [10]

  1. A conserved N-terminal domain containing a cysteine rich region (12 cysteine residues) with multiple intra-domain disulfide bonds, an IGFBP motif (GCGCCXXC), the primary site of IGF binding.
  2. A highly variable central or linker domain (only 15% conservation between IGFBPs).
  3. A conserved C-terminal domain containing secondary IGF binding residues, a cysteine rich region (6 cysteine residues), an 18 residue basic motif that binds heparin, the acid labile subunit (ALS), and a nuclear localization sequence.

The linker domain is the site of most post-translational modification, which include glycosylation, phosphorylation, and limited proteolysis. By electrophoretic analysis IGFBP-3 appears as a doublet, owing to the occupancy of either two or three of its N-glycosylation sites by carbohydrate. Hypoglycosylated IGFBP-3 may be seen after extended glucose starvation.

Many proteases are known to cleave IGFBP-3 at single linker-domain sites, and in the circulation of pregnant women, IGFBP-3 is entirely proteolyzed, yet still capable of carrying normal amounts of IGF-1 and IGF-2. Binding capacity appears to be retained after proteolysis because of a cooperative interaction between the two proteolyzed fragments, that together maintain an active IGF-binding site. [11]

Sites and regulation of production

IGFBP-3 mRNA is expressed in all tissue examined, with kidney, stomach, placenta, uterus and liver showing highest expression in rat tissues. [12] Rat liver IGFBP-3 mRNA is found in nonparenchymal cells including sinusoidal endothelium, but not in hepatocytes. [13] In contrast, human hepatocytes do express IGFBP-3. [14]

IGFBP-3 levels in human serum are, like IGF-1, dependent on growth hormone (GH); for example, serum IGFBP-3 is increased in acromegaly and low in GH-deficient children. However, IGFBP-3 gene expression in human liver is GH-independent. [7] [15] Because it is stabilized in human serum by forming complexes with IGF-1 and ALS, which are both GH-dependent, serum IGFBP-3 also appears regulated by GH. Its production by some non-hepatic tissues may also be directly GH-regulated. Immunoassays for serum IGFBP-3 are often used as part of the diagnosis of childhood GH-deficiency.

The most widely studied IGFBP3 polymorphism, at nucleotide-202 in the promoter region, is significantly associated with circulating IGFBP-3 levels, although the mechanism is unclear. [16] In some studies circulating IGFBP-3 also appears to be nutritionally regulated, although this may not be seen at the mRNA level. IGFBP-3 has been identified in human lymph, nipple aspirate, milk, amniotic fluid, follicular fluid, seminal plasma, urine, peritoneal dialysate, synovial fluid, tear fluid, and cerebrospinal fluid, in addition to serum.

Many factors increase IGFBP-3 production by cells, including transforming growth factor-β (TGFβ), tumor necrosis factor-α, vitamin D, retinoic acid, IGF-1, and stimuli such as chemotherapy that activate the tumor suppressor p53. [17] Estrogen inhibits IGFBP-3 production, and its tissue levels are lower in estrogen receptor (ER)-positive breast cancers than in ER-negative cancers.

Interactions

The main IGFBP-3 ligands in the circulation are IGF-1 and IGF-2, and the acid-labile subunit (ALS). [18] The serum proteins transferrin, [19] fibronectin, [20] and plasminogen [21] are also known to bind IGFBP-3. In the cell and tissue environment many other interactions have been described (see Table). Two unrelated cell-surface proteins have been designated as IGFBP-3 receptors: low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor or type V TGFβ receptor [22] and the transmembrane protein TMEM219. [23] Both are believed to mediate antiproliferative effects. Functional interactions with the EGF receptor and the type I/type II TGFβ receptor system have also been reported, and other cell-surface proteins such as proteoglycans also bind IGFBP-3. IGFBP-3 can enter cells by both clathrin-mediated and caveolin-mediated endocytosis. [24] possibly involving the transferrin receptor. [25]

IGFBP-3 enters the cell nucleus by a mechanism that is incompletely understood, but involves its binding to importin-β. [26] Within the nucleus, it can modulate nuclear hormone receptor activity by direct binding to retinoid X receptor, retinoic acid receptor, [27] vitamin D receptor, [28] PPARγ, [29] and nur77, [30] IGFBP-3 also interacts with DNA-dependent protein kinase within the nucleus to promote the repair of DNA damage. [31]

Cellular actions

IGFBP-3 exerts antiproliferative effects in many cell types by blocking the ability of IGF-1 and IGF-2 to activate the IGF1R (which stimulates cell proliferation). For example, in esophageal epithelial cells, responsiveness to IGF-1 stimulation is suppressed by secreted IGFBP-3 and restored when IGFBP-3 is downregulated by epidermal growth factor. [32] IGFBP-3 can also inhibit cell function by mechanisms that are independent of effects on IGF1R signaling, even in cells that entirely lack IGF1R. [33] IGF (or IGF1R) independent effects are commonly studied using mutant forms of IGFBP-3 with decreased IGF binding affinity. Thus, IGFBP-3-induced apoptosis in differentiating chondrocyte precursor cells is seen equally with a non-IGF binding IGFBP-3 mutant, demonstrating that the mechanism does not involve IGF binding. [34] IGF1R-independent growth inhibition by IGFBP-3 may involve the induction of pro-apoptotic proteins such as Bax and Bad [35] and may be mediated by ceramides (pro-apoptotic lipids), [36] or potentiate ceramide action [37] IGFBP-3 interaction with nuclear hormone receptors may also lead to inhibition of cell proliferation.

Contrasting with the typical growth-inhibitory effects of IGFBP-3, stimulation of cell proliferation by IGFBP-3 has also been observed. This can occur either by enhancing IGF-stimulated proliferation [38] or in the absence of IGF-1. In endothelial cells and mammary epithelial cells, the stimulatory effect of IGFBP-3 has been shown to involve activation of the enzyme sphingosine kinase, and generation of the bioactive lipid, sphingosine-1-phosphate, which promotes growth by transactivating the EGFR receptor. [36] [39]

Role in cancer

Based on cell growth experiments, animal cancer models, and epidemiological studies, it appears that IGFBP-3 functions as a low-penetrance tumor suppressor gene. [10]

Dysregulation of IGFBP-3 has been implicated in many cancers. [40] Downregulation of its tissue expression by promoter hypermethylation in some cancers, such as hepatoma [41] and non-small cell lung cancer [42] may be associated with poor patient outcome. However, consistent with the dual inhibitory and stimulatory roles of IGFBP-3 seen in cell culture, there are other cancer types, such as breast cancer, [43] [44] pancreatic cancer, [45] and clear cell renal cell cancer [46] in which high tissue IGFBP-3 expression has been linked to poor prognostic features or patient outcome. The mechanisms regulating these contrasting effects of IGFBP-3 in vivo are not well understood.

Since IGFBP-3 is abundant in the bloodstream of healthy adults (typically 2–4 mg/L), and is largely stabilized by its complex formation with IGFs and ALS, it is unlikely that tumor-derived IGFBP-3 has a large influence on circulating levels. There have been many studies linking circulating IGFBP-3 levels to the presence, or risk, of various cancers, or to patient outcomes. [40] but unequivocal conclusions have often been lacking. For example, high plasma IGFBP-3 levels were associated with a reduced prospective risk of colorectal cancer in women. [47] but in a study including men and women, colon cancer risk was positively associated with plasma IGFBP-3, while there was no significant association for rectal cancer. [48] A large systematic review concluded that circulating IGFBP-3 levels showed a modest association with increased risk for a number of cancers, but the results vary among sites. [49]

IGFBP-3 protein levels decrease during the progression of prostate cancer from benign to metastatic disease [50] although production of the protein does not cease completely. IGFBP-3 is still made (at a lower level) by prostate cancer cells and secreted into the surrounding environment. However, instead of the full length, functional protein, IGFBP-3 is found to be cleaved. [51] This decreases the affinity of IGF binding to IGFBP-3, making the growth factors more likely to bind the IGF1R and promote cell survival.

Table: IGFBP-3 binding partners

IGFBP3 has been shown to interact with:

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor</span> Proteins similar to insulin that stimulate cell proliferation

The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors, two ligands, a family of seven high-affinity IGF-binding proteins, as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

<span class="mw-page-title-main">Insulin receptor</span> Cell receptor found in humans

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein found in humans

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro, and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

<span class="mw-page-title-main">Sex hormone-binding globulin</span> Human glycoprotein that binds to androgens and estrogens

Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding protein (ABP).

<span class="mw-page-title-main">Insulin-like growth factor 2</span> Protein hormone

Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the blood. It has growth-regulating, insulin-like and mitogenic activities. The growth factor has a major, but not absolute, dependence on somatotropin. It is believed to be a major fetal growth factor in contrast to insulin-like growth factor 1 (IGF-1), which is a major growth factor in adults."

<span class="mw-page-title-main">Insulin-like growth factor 1 receptor</span> Cell receptor protein found in humans

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

<span class="mw-page-title-main">Insulin-like growth factor-binding protein</span> Transport protein for insulin-like growth factor 1

The insulin-like growth factor-binding protein (IGFBP) serves as a transport protein for insulin-like growth factor 1 (IGF-1).

<span class="mw-page-title-main">Laron syndrome</span> Medical condition

Laron syndrome (LS), also known as growth hormone insensitivity or growth hormone receptor deficiency (GHRD), is an autosomal recessive disorder characterized by a lack of insulin-like growth factor 1 production in response to growth hormone. It is usually caused by inherited growth hormone receptor (GHR) mutations.

Growth hormone-binding protein (GHBP) is a soluble carrier protein for growth hormone (GH). The full range of functions of GHBP remains to be determined however, current research suggests that the protein is associated with regulation of the GH availability and half-life in the circulatory system, as well as modulating GH receptor function.

<span class="mw-page-title-main">Insulin-like growth factor 2 receptor</span> Protein found in humans

Insulin-like growth factor 2 receptor (IGF2R), also called the cation-independent mannose-6-phosphate receptor (CI-MPR) is a protein that in humans is encoded by the IGF2R gene. IGF2R is a multifunctional protein receptor that binds insulin-like growth factor 2 (IGF2) at the cell surface and mannose-6-phosphate (M6P)-tagged proteins in the trans-Golgi network.

<span class="mw-page-title-main">Insulin receptor substrate 1</span> Protein found in humans

Insulin receptor substrate 1(IRS-1) is a signaling adapter protein that in humans is encoded by the IRS1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.

<span class="mw-page-title-main">IGFBP2</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 2 is a protein that in humans is encoded by the IGFBP2 gene.

<span class="mw-page-title-main">IGFBP5</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 5(IBF-5) is a protein that in humans is encoded by the IGFBP5 gene. An IGFBP5 gene was recently identified as being important for adaptation to varying water salinity in fish.

<span class="mw-page-title-main">IGFBP4</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 4 is a protein that in humans is encoded by the IGFBP4 gene.

<span class="mw-page-title-main">IGFBP6</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 6 (IGFBP-6) is a protein that in humans is encoded by the IGFBP6 gene.

<span class="mw-page-title-main">IGFBP1</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 1 (IBP-1) also known as placental protein 12 (PP12) is a protein that in humans is encoded by the IGFBP1 gene.

<span class="mw-page-title-main">IGFBP7</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with low affinity compared to IGFBPs 1-6. It also stimulates cell adhesion. The protein is implicated in some cancers.

<span class="mw-page-title-main">IGFALS</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor binding protein, acid labile subunit, also known as IGFALS, is a protein which in humans is encoded by the IGFALS gene.

Dalotuzumab is an anti-IGF1 receptor (IGF1R) humanized monoclonal antibody designed for the potential treatment of various cancers. Common adverse effects include hyperglycemia, nausea, vomiting, and fatigue. Dalotuzumab was developed by Merck and Co., Inc.

<span class="mw-page-title-main">Cyclic glycine-proline</span> Small neuroactive peptide

Cyclic glycine-proline (cGP) is a small neuroactive peptide that belongs to a group of bioactive 2,5-diketopiperazines (2,5-DKPs) and is also known as cyclo-glycine-proline. cGP is a neutral, stable naturally occurring compound and is endogenous to the human body; found in human plasma, breast milk and cerebrospinal fluid. DKPs are bioactive compounds often found in foods. Cyclic dipeptides such as 2,5 DKPs are formed by the cyclisation of two amino acids of linear peptides produced in heated or fermented foods. The bioactivity of cGP is a property of functional foods and presents in several matrices of foods including blackcurrants.

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