Insulin-like growth factor

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3GF1 insulin-like growth factor macromolecular structure 3GF1 Insulin-Like Growth Factor Nmr 10 01.png
3GF1 insulin-like growth factor
macromolecular structure

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 (often referred to as the IGF "axis") consists of two cell-surface receptors (IGF1R and IGF2R), two ligands (IGF-1 and IGF-2), a family of seven high-affinity IGF-binding proteins (IGFBP1 to IGFBP7), as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

Contents

IGF1/GH axis

The IGF "axis" is also commonly referred to as the Growth Hormone/IGF-1 Axis. Insulin-like growth factor 1 (commonly referred to as IGF-1 or at times using Roman numerals as IGF-I) is mainly secreted by the liver as a result of stimulation by growth hormone (GH). IGF-1 is important for both the regulation of normal physiology, as well as a number of pathological states, including cancer. The IGF axis has been shown to play roles in the promotion of cell proliferation and the inhibition of cell death (apoptosis).

Insulin-like growth factor 2 (IGF-2, at times IGF-II) is thought to be a primary growth factor required for early development while IGF-1 expression is required for achieving maximal growth. Gene knockout studies in mice have confirmed this, though other animals are likely to regulate the expression of these genes in distinct ways. While IGF-2 may be primarily fetal in action it is also essential for development and function of organs such as the brain, liver, and kidney. [1]

Factors that are thought to cause variation in the levels of GH and IGF-1 in the circulation include an individual's genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level, body mass index (BMI), disease state, race, estrogen status, and xenobiotic intake. [2] [3] [4]

IGF-1 has an involvement in regulating neural development including neurogenesis, myelination, synaptogenesis, and dendritic branching and neuroprotection after neuronal damage. Increased serum levels of IGF-I in children have been associated with higher IQ. [5]

IGF-1 shapes the development of the cochlea through controlling apoptosis. Its deficit can cause hearing loss. Serum level of it also underlies a correlation between short height and reduced hearing abilities particularly around 3–5 years of age, and at age 18 (late puberty). [6]

IGF receptors

The IGFs are known to bind the IGF-1 receptor, the insulin receptor, the IGF-2 receptor, the insulin-related receptor and possibly other receptors. The IGF-1 receptor is the "physiological" receptor. IGF-1 binds to it at significantly higher affinity than it binds the insulin receptor. Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase—meaning the receptor signals by causing the addition of a phosphate molecule on particular tyrosines. The IGF-2 receptor only binds IGF-2 and acts as a "clearance receptor"—it activates no intracellular signaling pathways, functioning only as an IGF-2 sequestering agent and preventing IGF-2 signaling. [7]

Organs and tissues affected by IGF-1

Since many distinct tissue types express the IGF-1 receptor, IGF-1's effects are diverse. It acts as a neurotrophic factor, inducing the survival of neurons. It may catalyse skeletal muscle hypertrophy, by inducing protein synthesis, and by blocking muscle atrophy. It is protective for cartilage cells, and is associated with activation of osteocytes, and thus may be an anabolic factor for bone. Since at high concentrations it is capable of activating the insulin receptor, it can also complement for the effects of insulin. [8] Receptors for IGF-1 are found in vascular smooth muscle, while typical receptors for insulin are not found in vascular smooth muscle. [9]

IGF-binding proteins

IGF-1 and IGF-2 are regulated by a family of proteins known as the IGF-binding proteins. These proteins help to modulate IGF action in complex ways that involve both inhibiting IGF action by preventing binding to the IGF-1 receptor as well as promoting IGF action possibly through aiding in delivery to the receptor and increasing IGF half-life. Currently, there are seven characterized IGF Binding Proteins (IGFBP1 to IGFBP7). There is currently significant data suggesting that IGFBPs play important roles in addition to their ability to regulate IGFs. IGF-1 and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. IGFBP-1 production from the liver is significantly elevated during insulinopenia while serum levels of bioactive IGF-1 is increased by insulin. [10]

Diseases affected by IGF

Studies of recent interest show that the Insulin/IGF axis play an important role in aging. [11] Nematodes, fruit-flies, and other organisms have an increased life span when the gene equivalent to the mammalian insulin is knocked out. It is somewhat difficult to relate this finding to the mammals, however, because in the smaller organism there are many genes (at least 37 in the nematode Caenorhabditis elegans [12] ) that are "insulin-like" or "IGF-1-like", whereas in the mammals insulin-like proteins comprise only seven members (insulin, IGFs, relaxins, EPIL, and relaxin-like factor). [13] The human insulin-like genes have apparently distinct roles with some but less crosstalk presumably because there are multiple insulin-receptor-like proteins in humans. Simpler organisms typically have fewer receptors; for example, only one insulin-like receptor exists in the nematode C. elegans. [14] Additionally, C. elegans do not have specialized organs such as the (Islets of Langerhans), which sense insulin in response to glucose homeostasis. Moreover, IGF1 affects lifespan in nematodes by causing dauer formation, a developmental stage of C. elegans larva. There is no mammalian correlate. Therefore, it is an open question as to whether either IGF-1 or insulin in the mammal may perturb aging, although there is the suggestion that dietary restriction phenomena may be related. [15]

Other studies are beginning to uncover the important role the IGFs play in diseases such as cancer and diabetes, showing for instance that IGF-1 stimulates growth of both prostate and breast cancer cells. Researchers are not in complete agreement about the degree of cancer risk that IGF-1 poses. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein-coding gene in the species Homo sapiens

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.

<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">Relaxin</span> Protein hormone

Relaxin is a protein hormone of about 6000 Da, first described in 1926 by Frederick Hisaw.

<span class="mw-page-title-main">Insulin-like growth factor 1 receptor</span> Cell surface tyrosine kinase associated receptor, quiche mediates the effects of Igf-1

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">IGFBP3</span> Protein-coding gene in the species Homo sapiens

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 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.

<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">Relaxin/insulin-like family peptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Relaxin/insulin-like family peptide receptor 1, also known as RXFP1, is a human G protein coupled receptor that is one of the relaxin receptors. It is a rhodopsin-like GPCR which is unusual in this class as it contains a large extracellular binding and signalling domain. Some reports suggest that RXFP1 forms homodimers, however the most recent evidence indicates that relaxin binds a non-homodimer of RXFP1.

<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">Daf-16</span> Ortholog

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism.

<span class="mw-page-title-main">Relaxin family peptide hormones</span> Protein family

Relaxin family peptide hormones in humans are represented by seven members: three relaxin-like (RLN) and four insulin-like (INSL) peptides: RLN1, RLN2, RNL3, INSL3, INSL4, INSL5, INSL6. This subdivision into two classes is based primarily on early findings, and does not reflect the evolutionary origins or physiological differences between peptides. For example, it is known that the genes coding for RLN3 and INSL5 arose from one ancestral gene, and INSL3 shares origin with RLN2 and its multiple duplicates: RLN1, INSL4, INSL6.

Long arginine 3-IGF-1, abbreviated as IGF-1 LR3 or LR3-IGF-1, is a synthetic protein and lengthened analogue of human insulin-like growth factor 1 (IGF-1). It differs from native IGF-1 in that it possesses an arginine instead of a glutamic acid at the third position in its amino acid sequence, and also has an additional 13 amino acids at its N-terminus (MFPAMPLLSLFVN) ("long"), for a total of 83 amino acids. The consequences of these modifications are that IGF-1 LR3 retains the pharmacological activity of IGF-1 as an agonist of the IGF-1 receptor, has very low affinity for the insulin-like growth factor-binding proteins (IGFBPs), and has improved metabolic stability. As a result, it is approximately three times more potent than IGF-1, and possesses a significantly longer half-life of about 20–30 hours.

<span class="mw-page-title-main">Age-1</span> Gene

The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants. The age-1 mutant, first identified by Michael Klass, was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al. Development, metabolism, lifespan, among other processes have been associated with age-1 expression. The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms. Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.

<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.

References

  1. ↑ Younis, Shady (February 27, 2018). "The ZBED6–IGF2 axis has a major effect on growth of skeletal muscle and internal organs in placental mammals". PNAS. 9 (115): E2048–E2057. Bibcode:2018PNAS..115E2048Y. doi: 10.1073/pnas.1719278115 . PMC   5834713 . PMID   29440408.
  2. ↑ Takahashi Y, Kipnis DM, Daughaday WH (September 1968). "Growth hormone secretion during sleep". The Journal of Clinical Investigation. 47 (9): 2079–90. doi:10.1172/JCI105893. PMC   297368 . PMID   5675428.
  3. ↑ Giustina A, Mazziotti G, Canalis E (August 2008). "Growth hormone, insulin-like growth factors, and the skeleton". Endocrine Reviews. 29 (5): 535–59. doi:10.1210/er.2007-0036. PMC   2726838 . PMID   18436706.
  4. ↑ Sutton J, Lazarus L (October 1976). "Growth hormone in exercise: comparison of physiological and pharmacological stimuli". Journal of Applied Physiology. 41 (4): 523–7. doi:10.1152/jappl.1976.41.4.523. PMID   985395.
  5. ↑ Gunnell D, Miller LL, Rogers I, Holly JM (November 2005). "Association of insulin-like growth factor I and insulin-like growth factor-binding protein-3 with intelligence quotient among 8- to 9-year-old children in the Avon Longitudinal Study of Parents and Children". Pediatrics. 116 (5): e681-6. doi:10.1542/peds.2004-2390. PMID   16263982.
  6. ↑ Welch D, Dawes PJ (October 2007). "Childhood hearing is associated with growth rates in infancy and adolescence". Pediatric Research. 62 (4): 495–8. doi: 10.1203/PDR.0b013e3181425869 . PMID   17667854.
  7. ↑ Rosenzweig, Steven A.; Atreya, Hanudatta S. (2010-10-15). "Defining the pathway to insulin-like growth factor system targeting in cancer". Biochemical Pharmacology. 80 (8): 1115–1124. doi:10.1016/j.bcp.2010.06.013. ISSN   0006-2952. PMC   2934757 . PMID   20599789.
  8. ↑ Boucher, Jeremie; Tseng, Yu-Hua; Kahn, C. Ronald (2010-05-28). "Insulin and Insulin-like Growth Factor-1 Receptors Act as Ligand-specific Amplitude Modulators of a Common Pathway Regulating Gene Transcription". The Journal of Biological Chemistry. 285 (22): 17235–17245. doi: 10.1074/jbc.M110.118620 . ISSN   0021-9258. PMC   2878077 . PMID   20360006.
  9. ↑ Bornfeldt KE, Arnqvist HJ, Dahlkvist HH, Skottner A, Wikberg JE (April 1988). "Receptors for insulin-like growth factor-I in plasma membranes isolated from bovine mesenteric arteries". Acta Endocrinologica. 117 (4): 428–34. doi:10.1530/acta.0.1170428. PMID   2968745.
  10. ↑ Brismar, K.; Fernqvist-Forbes, E.; Wahren, J.; Hall, K. (1994). "Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes". The Journal of Clinical Endocrinology and Metabolism. 79 (3): 872–878. doi:10.1210/jcem.79.3.7521354. ISSN   0021-972X. PMID   7521354.
  11. ↑ Kenyon CJ (March 2010). "The genetics of ageing". Nature. 464 (7288): 504–12. Bibcode:2010Natur.464..504K. doi:10.1038/nature08980. PMID   20336132. S2CID   2781311.
  12. ↑ Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, et al. (March 2001). "Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family". Genes & Development. 15 (6): 672–86. doi:10.1101/gad.867301. PMC   312654 . PMID   11274053.
  13. ↑ Honnen, Sebastian J.; Büchter, Christian; Schröder, Verena; Hoffmann, Michael; Kohara, Yuji; Kampkötter, Andreas; Bossinger, Olaf (2012-02-16). "C. elegans VANG-1 Modulates Life Span via Insulin/IGF-1-Like Signaling". PLOS ONE. 7 (2): e32183. Bibcode:2012PLoSO...732183H. doi: 10.1371/journal.pone.0032183 . ISSN   1932-6203. PMC   3281126 . PMID   22359667.
  14. ↑ Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (August 1997). "daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans". Science. 277 (5328): 942–6. doi:10.1126/science.277.5328.942. PMID   9252323.
  15. ↑ Venz, Richard; Pekec, Tina; Katic, Iskra; Ciosk, Rafal; Ewald, Collin Yvès (2021-09-10). "End-of-life targeted degradation of DAF-2 insulin/IGF-1 receptor promotes longevity free from growth-related pathologies". eLife. 10: e71335. doi: 10.7554/eLife.71335 . ISSN   2050-084X. PMC   8492056 . PMID   34505574.
  16. ↑ Woods AG, Guthrie KM, Kurlawalla MA, Gall CM (April 1998). "Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats". Neuroscience. 83 (3): 663–8. doi:10.1016/S0306-4522(97)00539-3. PMID   9483550. S2CID   208782267.
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