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IGF1 (Insulin-Like Growth Factor 1 (Somatomedin C))

Written2013-11Nicholas D Panayi, Randy Burd
Department of Nutritional Sciences, College of Medicine, University of Arizona, Tucson, AZ 85721, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesinsulin-like growth factor 1 (somatomedin C)
Alias_symbol (synonym)IGF1A
IGFI
IGF-I
Other alias
HGNC (Hugo) IGF1
LocusID (NCBI) 3479
Atlas_Id 40927
Location 12q23.2  [Link to chromosome band 12q23]
Location_base_pair Starts at 102395867 and ends at 102480645 bp from pter ( according to hg19-Feb_2009)  [Mapping IGF1.png]
Fusion genes
(updated 2016)
RBM3 (Xp11.23) / IGF1 (12q23.2)

DNA/RNA

 
  Illustrates IGF-1 splice sites and isoform variants (adapted from Mills et al., 2007).
Description Genomic size: 84779 bp. The IGF-1 Gene is composed of 6 different exons. Exons 1 and 2 determine the class of the protein and functionally represent the signal peptide for cellular localization post-translation. Exons 3 and 4 will primarily encode the IGF-1 mature peptide; ultimately becoming the receptor binding ligand. Exons 5 and 6 will primarily represent the E domain peptide; with exon six providing the different polyadenylating signals. These parts of the transcript give a functional distinction to the 6 isoforms produced (although such distinctions have yet to be definitively identified) (Adapted from Mills et al., 2007; Philippou et al., 2007).
Transcription Six different heterogeneous mRNA are transcribed using alternate promoters, alternate splice sites and varying polyadenylation signals. Class one and two are derived from the exon one and two promoter respectively; both are differentially spliced to the common three exon. Each class can be variably spliced to the fifth and sixth exons, producing a total of six different isoforms (Philippou et al., 2007).
Class one isoforms predominate in the extrahepatic tissues and are secreted in a paracrine/autocrine fashion.
Class two isoforms predominate in the liver and are secreted in an endocrine fashion. They are also more sensitive or responsive to growth hormone relative to class 1 (Mills et al., 2007).
Individual isoforms may be more favorably translated depending on the tissue type, the available binding proteins and the physiological context.
Researchers are discovering evidence that suggest certain isoforms may be preferentially expressed under varying amounts of mechanical pressure in skeletal muscle (Philippou et al., 2007). The advantages of one isoform or another, in varying contexts of stress, inflammation, regeneration and hypertrophy are yet to be elucidated.
Pseudogene Not reported.

Protein

Description Single polypeptide chain protein consisting of 70 amino acids and three disulfide bridges.
Expression It is primarily produced and secreted in endocrine fashion by the liver. It is also produced and secreted in autocrine or paracrine fashion in a wide range of extra-hepatic tissues. Tissues produce IGF-1 protein in response to growth hormone during periods of pre/post-natal development, exercise and injury. Inhibited in undernourished states, low protein, growth hormone deficiency and growth hormone receptor insensitivity (Cheng et al., 2006).
Localisation The protein is post-translationally modified by protease cleavage of the signal and E-peptide. The mature protein subsequently binds to one of six binding proteins and is then secreted form the tissue of origin (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6). IGFBP3 predominates, binding to 80% of the available IGF-1. The binding proteins increase the half life of IGF, preventing renal clearance and inactivation. IGFBP (1,3,4,6) are growth promoting; IGFBP-(2,5) bind IGF-1 and limit IGFR/IGF-1 interaction; a growth inhibiting effect.
Function Important for growth/development in children and adults. Vital role in anabolic processes in general. Important functions in osteogenesis, axonal generation in nerves, nerve regeneration after ischemic insult, muscle repair and hypertrophy after trauma or exercise (Cheng et al., 2006). Although still under investigation, studies suggest that individual isotype/binding protein combinations manifest in response to specific environmental interactions or physiological demands. In addition, the binding proteins are critical for maintaining the bioavailability of the IGF-1. The unique IGF-1/IGF-1 receptor complex will then signal the protein cascade necessary for tissue metabolism or regeneration. Ischemic damage to the brain illustrates how this concept materializes. Cytotoxic edema and inflammatory markers induce the transcription of a specific isotype; which then binds to a tissue specific binding protein; protecting the integrity of the protein and preventing its renal clearance. The distinctive IGF-1/IGF-1R complex will then activate the protein kinase cascade necessary for axonal regeneration.
Cellular/molecular effects: Upon binding, the tyrosine kinase receptor, IGF-1/IGF-1R complex activates the PI3K/AKT/mTOR and RAS/RAF/MAPK protein cascades. Both interfere with apoptosis and are pro-cell survival; the latter additionally promotes cellular differentiation, metabolism, growth and repair. Given its integral utility in tissue growth, repair and cell cycle regulation, IGF-1 receptors are found ubiquitously throughout the body and include: muscle, bone, cartilage, kidney, liver, lung and nervous tissue (Schiaffino et al., 2011).
It is speculated that binding proteins may not only enhance or subdue IGF-1/IGF-1R interaction but help specify which isoform should predominate.
Biotech and Clinical Application: Recombinant IGF-1 expressed in e. Coli is being tested either for symptomatic relief, tissue regeneration or penetrance reduction in the following diseases or conditions:
- Laron's Dwarfism
- Duchenne's Muscular Dystrophy
- Amyotrophic Lateral Sclerosis
- Post ischemic damage to brain (stroke)
- Diabetes and Insulin Insensitivity
Homology Shares some sequence homology to insulin and has a relatively weak affinity to insulin receptors.

Implicated in

Note
  
Entity Various cancers
Note No specific mutations of IGF-1 have been connected to genetically acquired diseases. Despite this fact, certain haplotypes of IGF-1 have been implicated in the survival of solid tumors. It is postulated that IGF-1 has tumor promoting effects when its cellular growth/anti-apoptotic functions become dysregulated (see oncogenesis below). Additionally it plays a critical role in the clinical sequelae of Laron's dwarfism (see below).
Disease High levels implicated in the survival of solid tumors and Acromegaly. Low levels of IGF-1/IGFBP3 consistently found in Laron's Dwarfism; An Autosomal recessive disease caused by a mutation in the growth hormone receptor; causing poor ligand interaction with growth hormone and subsequent low levels of IGF-1.
Prognosis Individuals with Laron's are dwarfs with characteristic facial and anatomical anomalies (flat nasal bridge, prominent forehead, obesity, small mandible and phallus). They also exhibit seizures secondary to hypoglycemia. Unlike Achondroplasia, Laron's Dwarfism does not respond to GH. Laron Dwarfs have a greater resistance to diabetes, cancer and age progression; underscoring the function of IGF-1 and its critical role in cellular metabolism and cell cycle maintenance (Melnik et al., 2011).
 
IGF-1 mediated signal transduction (adapted from Schiaffino, S. et. al, 2011).
Oncogenesis IGF-1 signaling through RAS/RAF/MAPK and has been demonstrated to promote breast cancer and prostate tumorigenesis. IGF-1/IGF-R interaction induces the transcription of survival/ growth enhancing genes. Signaling through these pathways results in increased cellular proliferation and anti-apoptotic effects; promoting a favorable environment for tumor growth. In General, high levels of IGF-1 are found in solid tumors (particularly breast and prostate). Certain SNP's and IGF-1 haplotypes have been associated with increased risk of colon, pancreatic, prostate and breast cancer. It is likely that specific haplotypes in combination with other variables can create a more favorable tumorigenic environment. i.e. Individuals with a BMI>25, containing specific IGF-1 haplotypes may have a greater risk of developing pancreatic cancer (Cheng et al., 2006).
  

Bibliography

Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort.
Cheng I, Stram DO, Penney KL, Pike M, Le Marchand L, Kolonel LN, Hirschhorn J, Altshuler D, Henderson BE, Freedman ML.
J Natl Cancer Inst. 2006 Jan 18;98(2):123-34.
PMID 16418515
 
Over-stimulation of insulin/IGF-1 signaling by western diet may promote diseases of civilization: lessons learnt from laron syndrome.
Melnik BC, John SM, Schmitz G.
Nutr Metab (Lond). 2011 Jun 24;8:41. doi: 10.1186/1743-7075-8-41.
PMID 21699736
 
A synthetic mechano growth factor E Peptide enhances myogenic precursor cell transplantation success.
Mills P, Dominique JC, Lafreniere JF, Bouchentouf M, Tremblay JP.
Am J Transplant. 2007 Oct;7(10):2247-59.
PMID 17845560
 
The role of the insulin-like growth factor 1 (IGF-1) in skeletal muscle physiology.
Philippou A, Maridaki M, Halapas A, Koutsilieris M.
In Vivo. 2007 Jan-Feb;21(1):45-54. (REVIEW)
PMID 17354613
 
Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models.
Schiaffino S, Mammucari C.
Skelet Muscle. 2011 Jan 24;1(1):4. doi: 10.1186/2044-5040-1-4.
PMID 21798082
 

Citation

This paper should be referenced as such :
Panayi, ND ; Burd, R
IGF1 (Insulin-Like Growth Factor 1 (Somatomedin C))
Atlas Genet Cytogenet Oncol Haematol. 2014;18(6):378-380.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/IGF1ID40927ch12q23.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Multiple Myeloma in 2017


External links

Nomenclature
HGNC (Hugo)IGF1   5464
Cards
AtlasIGF1ID40927ch12q23
Entrez_Gene (NCBI)IGF1  3479  insulin like growth factor 1
AliasesIGF-I; IGFI; MGF
GeneCards (Weizmann)IGF1
Ensembl hg19 (Hinxton)ENSG00000017427 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000017427 [Gene_View]  chr12:102395867-102480645 [Contig_View]  IGF1 [Vega]
ICGC DataPortalENSG00000017427
TCGA cBioPortalIGF1
AceView (NCBI)IGF1
Genatlas (Paris)IGF1
WikiGenes3479
SOURCE (Princeton)IGF1
Genetics Home Reference (NIH)IGF1
Genomic and cartography
GoldenPath hg38 (UCSC)IGF1  -     chr12:102395867-102480645 -  12q23.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)IGF1  -     12q23.2   [Description]    (hg19-Feb_2009)
EnsemblIGF1 - 12q23.2 [CytoView hg19]  IGF1 - 12q23.2 [CytoView hg38]
Mapping of homologs : NCBIIGF1 [Mapview hg19]  IGF1 [Mapview hg38]
OMIM147440   608747   
Gene and transcription
Genbank (Entrez)AB209184 AK312231 AL603526 AL710591 BC148266
RefSeq transcript (Entrez)NM_000618 NM_001111283 NM_001111284 NM_001111285
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)IGF1
Cluster EST : UnigeneHs.160562 [ NCBI ]
CGAP (NCI)Hs.160562
Alternative Splicing GalleryENSG00000017427
Gene ExpressionIGF1 [ NCBI-GEO ]   IGF1 [ EBI - ARRAY_EXPRESS ]   IGF1 [ SEEK ]   IGF1 [ MEM ]
Gene Expression Viewer (FireBrowse)IGF1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3479
GTEX Portal (Tissue expression)IGF1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP05019   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP05019  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP05019
Splice isoforms : SwissVarP05019
PhosPhoSitePlusP05019
Domaine pattern : Prosite (Expaxy)INSULIN (PS00262)   
Domains : Interpro (EBI)IGF-I    Insulin-like    Insulin-like_growth_factor    Insulin_CS    Insulin_family   
Domain families : Pfam (Sanger)Insulin (PF00049)   
Domain families : Pfam (NCBI)pfam00049   
Domain families : Smart (EMBL)IlGF (SM00078)  
Conserved Domain (NCBI)IGF1
DMDM Disease mutations3479
Blocks (Seattle)IGF1
PDB (SRS)1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
PDB (PDBSum)1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
PDB (IMB)1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
PDB (RSDB)1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
Structural Biology KnowledgeBase1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
SCOP (Structural Classification of Proteins)1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
CATH (Classification of proteins structures)1B9G    1BQT    1GF1    1GZR    1GZY    1GZZ    1H02    1H59    1IMX    1PMX    1TGR    1WQJ    2DSP    2DSQ    2DSR    2GF1    3GF1    3LRI    4XSS   
SuperfamilyP05019
Human Protein AtlasENSG00000017427
Peptide AtlasP05019
HPRD00936
IPIIPI00433029   IPI00001610   IPI00852675   IPI00793994   IPI00853336   
Protein Interaction databases
DIP (DOE-UCLA)P05019
IntAct (EBI)P05019
FunCoupENSG00000017427
BioGRIDIGF1
STRING (EMBL)IGF1
ZODIACIGF1
Ontologies - Pathways
QuickGOP05019
Ontology : AmiGOactivation of MAPK activity  skeletal system development  cell activation  platelet degranulation  insulin receptor binding  insulin-like growth factor receptor binding  insulin-like growth factor receptor binding  insulin-like growth factor receptor binding  integrin binding  hormone activity  protein binding  extracellular region  extracellular region  extracellular space  plasma membrane  DNA replication  movement of cell or subcellular component  signal transduction  Ras protein signal transduction  muscle organ development  growth factor activity  cell proliferation  positive regulation of cell proliferation  positive regulation of cell proliferation  response to heat  glycolate metabolic process  regulation of gene expression  positive regulation of glycoprotein biosynthetic process  positive regulation of cardiac muscle hypertrophy  positive regulation of cardiac muscle hypertrophy  phosphatidylinositol 3-kinase signaling  positive regulation of phosphatidylinositol 3-kinase signaling  skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration  muscle hypertrophy  myotube cell development  positive regulation of smooth muscle cell migration  insulin-like growth factor binding protein complex  proteoglycan biosynthetic process  proteoglycan biosynthetic process  positive regulation of cell migration  platelet alpha granule lumen  activation of protein kinase B activity  positive regulation of protein import into nucleus, translocation  negative regulation of smooth muscle cell apoptotic process  bone mineralization involved in bone maturation  alphav-beta3 integrin-IGF-1-IGF1R complex  regulation of multicellular organism growth  positive regulation of activated T cell proliferation  insulin-like growth factor ternary complex  negative regulation of apoptotic process  positive regulation of DNA binding  positive regulation of MAPK cascade  protein kinase B signaling  positive regulation of insulin-like growth factor receptor signaling pathway  cellular protein metabolic process  myoblast differentiation  positive regulation of osteoblast differentiation  positive regulation of glycogen biosynthetic process  positive regulation of DNA replication  positive regulation of DNA replication  positive regulation of glycolytic process  positive regulation of mitotic nuclear division  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of glucose import  positive regulation of Ras protein signal transduction  insulin-like growth factor receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of fibroblast proliferation  positive regulation of smooth muscle cell proliferation  positive regulation of epithelial cell proliferation  positive regulation of protein secretion  positive regulation of peptidyl-tyrosine phosphorylation  protein stabilization  myoblast proliferation  negative regulation of oocyte development  positive regulation of cell growth involved in cardiac muscle cell development  positive regulation of cell growth involved in cardiac muscle cell development  ERK1 and ERK2 cascade  exocytic vesicle  positive regulation of calcineurin-NFAT signaling cascade  negative regulation of release of cytochrome c from mitochondria  positive regulation of trophectodermal cell proliferation  positive regulation of transcription regulatory region DNA binding  negative regulation of extrinsic apoptotic signaling pathway  
Ontology : EGO-EBIactivation of MAPK activity  skeletal system development  cell activation  platelet degranulation  insulin receptor binding  insulin-like growth factor receptor binding  insulin-like growth factor receptor binding  insulin-like growth factor receptor binding  integrin binding  hormone activity  protein binding  extracellular region  extracellular region  extracellular space  plasma membrane  DNA replication  movement of cell or subcellular component  signal transduction  Ras protein signal transduction  muscle organ development  growth factor activity  cell proliferation  positive regulation of cell proliferation  positive regulation of cell proliferation  response to heat  glycolate metabolic process  regulation of gene expression  positive regulation of glycoprotein biosynthetic process  positive regulation of cardiac muscle hypertrophy  positive regulation of cardiac muscle hypertrophy  phosphatidylinositol 3-kinase signaling  positive regulation of phosphatidylinositol 3-kinase signaling  skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration  muscle hypertrophy  myotube cell development  positive regulation of smooth muscle cell migration  insulin-like growth factor binding protein complex  proteoglycan biosynthetic process  proteoglycan biosynthetic process  positive regulation of cell migration  platelet alpha granule lumen  activation of protein kinase B activity  positive regulation of protein import into nucleus, translocation  negative regulation of smooth muscle cell apoptotic process  bone mineralization involved in bone maturation  alphav-beta3 integrin-IGF-1-IGF1R complex  regulation of multicellular organism growth  positive regulation of activated T cell proliferation  insulin-like growth factor ternary complex  negative regulation of apoptotic process  positive regulation of DNA binding  positive regulation of MAPK cascade  protein kinase B signaling  positive regulation of insulin-like growth factor receptor signaling pathway  cellular protein metabolic process  myoblast differentiation  positive regulation of osteoblast differentiation  positive regulation of glycogen biosynthetic process  positive regulation of DNA replication  positive regulation of DNA replication  positive regulation of glycolytic process  positive regulation of mitotic nuclear division  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of glucose import  positive regulation of Ras protein signal transduction  insulin-like growth factor receptor signaling pathway  phosphatidylinositol-mediated signaling  positive regulation of fibroblast proliferation  positive regulation of smooth muscle cell proliferation  positive regulation of epithelial cell proliferation  positive regulation of protein secretion  positive regulation of peptidyl-tyrosine phosphorylation  protein stabilization  myoblast proliferation  negative regulation of oocyte development  positive regulation of cell growth involved in cardiac muscle cell development  positive regulation of cell growth involved in cardiac muscle cell development  ERK1 and ERK2 cascade  exocytic vesicle  positive regulation of calcineurin-NFAT signaling cascade  negative regulation of release of cytochrome c from mitochondria  positive regulation of trophectodermal cell proliferation  positive regulation of transcription regulatory region DNA binding  negative regulation of extrinsic apoptotic signaling pathway  
Pathways : BIOCARTA [Genes]   
Pathways : KEGG   
REACTOMEP05019 [protein]
REACTOME PathwaysR-HSA-422085 [pathway]   
NDEx NetworkIGF1
Atlas of Cancer Signalling NetworkIGF1
Wikipedia pathwaysIGF1
Orthology - Evolution
OrthoDB3479
GeneTree (enSembl)ENSG00000017427
Phylogenetic Trees/Animal Genes : TreeFamIGF1
HOVERGENP05019
HOGENOMP05019
Homologs : HomoloGeneIGF1
Homology/Alignments : Family Browser (UCSC)IGF1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerIGF1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)IGF1
dbVarIGF1
ClinVarIGF1
1000_GenomesIGF1 
Exome Variant ServerIGF1
ExAC (Exome Aggregation Consortium)IGF1 (select the gene name)
Genetic variants : HAPMAP3479
Genomic Variants (DGV)IGF1 [DGVbeta]
DECIPHERIGF1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisIGF1 
Mutations
ICGC Data PortalIGF1 
TCGA Data PortalIGF1 
Broad Tumor PortalIGF1
OASIS PortalIGF1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICIGF1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDIGF1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
BioMutasearch IGF1
DgiDB (Drug Gene Interaction Database)IGF1
DoCM (Curated mutations)IGF1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)IGF1 (select a term)
intoGenIGF1
NCG5 (London)IGF1
Cancer3DIGF1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM147440    608747   
Orphanet11048   
MedgenIGF1
Genetic Testing Registry IGF1
NextProtP05019 [Medical]
TSGene3479
GENETestsIGF1
Target ValidationIGF1
Huge Navigator IGF1 [HugePedia]
snp3D : Map Gene to Disease3479
BioCentury BCIQIGF1
ClinGenIGF1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3479
Chemical/Pharm GKB GenePA29697
Clinical trialIGF1
Miscellaneous
canSAR (ICR)IGF1 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineIGF1
EVEXIGF1
GoPubMedIGF1
iHOPIGF1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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