ASpdb: an integrative knowledgebase of human protein isoforms from experimental and AI-predicted structures

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	Protein Summary
	AS Summary
	Protein Functional Features
	Gene Isoform Structures and Expression Levels
	Protein Structures
	pLDDT Score Distribution
	Ramachandran Plot of Protein Structures
	Potential Active Site Information
	Protein Structure and Feature Comparision
	Protein-Protein Interaction
	Related Drugs
	Related Diseases
	Clinically Important Variants

Protein:IGF1

Protein Summary

Gene summary

Gene name: IGF1
ASpdb.0 ID: 3479
	Gene
Gene symbol	IGF1
Gene ID	3479
Gene name	insulin like growth factor 1
Synonyms	IGF\|IGF-I\|IGFI\|MGF
Cytomap	12q23.2
Type of gene	protein-coding
Description	insulin-like growth factor Iinsulin-like growth factor 1 (somatomedin C)insulin-like growth factor IBmechano growth factorsomatomedin-C
Modification date	20240416
UniProtAcc	P05019

Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Partner	Gene	GO ID	GO term	PubMed ID
Gene	IGF1	GO:0001775	cell activation	22797923
Gene	IGF1	GO:0005159	insulin-like growth factor receptor binding	19578119
Gene	IGF1	GO:0005178	integrin binding	19578119\|22351760
Gene	IGF1	GO:0005179	hormone activity	7188854
Gene	IGF1	GO:0005615	extracellular space	7188854\|11404306\|17119061\|25152160
Gene	IGF1	GO:0008284	positive regulation of cell population proliferation	7688386\|9722506\|12746903
Gene	IGF1	GO:0009408	response to heat	11404306
Gene	IGF1	GO:0010613	positive regulation of cardiac muscle hypertrophy	19654000
Gene	IGF1	GO:0010629	negative regulation of gene expression	29167509
Gene	IGF1	GO:0014834	skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration	17531227
Gene	IGF1	GO:0014904	myotube cell development	17531227
Gene	IGF1	GO:0014911	positive regulation of smooth muscle cell migration	10766744
Gene	IGF1	GO:0030166	proteoglycan biosynthetic process	12746903
Gene	IGF1	GO:0034392	negative regulation of smooth muscle cell apoptotic process	16942485
Gene	IGF1	GO:0035630	bone mineralization involved in bone maturation	16433617
Gene	IGF1	GO:0035867	alphav-beta3 integrin-IGF-1-IGF1R complex	19578119
Gene	IGF1	GO:0042060	wound healing	17531227
Gene	IGF1	GO:0042104	positive regulation of activated T cell proliferation	15694994
Gene	IGF1	GO:0042531	positive regulation of tyrosine phosphorylation of STAT protein	9722506
Gene	IGF1	GO:0042567	insulin-like growth factor ternary complex	9497324
Gene	IGF1	GO:0043388	positive regulation of DNA binding	19654000
Gene	IGF1	GO:0043410	positive regulation of MAPK cascade	19654000
Gene	IGF1	GO:0043568	positive regulation of insulin-like growth factor receptor signaling pathway	7688386\|10766744
Gene	IGF1	GO:0045445	myoblast differentiation	17531227
Gene	IGF1	GO:0045669	positive regulation of osteoblast differentiation	16433617
Gene	IGF1	GO:0045725	positive regulation of glycogen biosynthetic process	21076856
Gene	IGF1	GO:0045821	positive regulation of glycolytic process	7688386
Gene	IGF1	GO:0045840	positive regulation of mitotic nuclear division	7188854\|10644978
Gene	IGF1	GO:0045893	positive regulation of DNA-templated transcription	9722506\|19654000
Gene	IGF1	GO:0045944	positive regulation of transcription by RNA polymerase II	16433617
Gene	IGF1	GO:0046326	positive regulation of glucose import	21076856
Gene	IGF1	GO:0046579	positive regulation of Ras protein signal transduction	9722506
Gene	IGF1	GO:0048009	insulin-like growth factor receptor signaling pathway	7692086\|7782332
Gene	IGF1	GO:0048146	positive regulation of fibroblast proliferation	7188854
Gene	IGF1	GO:0048661	positive regulation of smooth muscle cell proliferation	10766744\|16942485
Gene	IGF1	GO:0050679	positive regulation of epithelial cell proliferation	7188854
Gene	IGF1	GO:0050731	positive regulation of peptidyl-tyrosine phosphorylation	22635104
Gene	IGF1	GO:0051450	myoblast proliferation	17531227
Gene	IGF1	GO:0051897	positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7688386\|7692086
Gene	IGF1	GO:0061051	positive regulation of cell growth involved in cardiac muscle cell development	24117217
Gene	IGF1	GO:0070886	positive regulation of calcineurin-NFAT signaling cascade	19654000
Gene	IGF1	GO:2000679	positive regulation of transcription regulatory region DNA binding	15059951
Gene	IGF1	GO:2001237	negative regulation of extrinsic apoptotic signaling pathway	16942485

AS Summary

Information of the canonical protein with experimentally identified structure from PDB (2023).

UniProt Acc	File name	PDB ID	Method	Resolution	Chain	Start	End
P05019-1	P05019-1_1h02_B.pdb	1H02	X-ray	2.0	B	51	116

ASpdb's canonical and alternatively spliced isoform information.

accession_id

gene_name

canonical_id

alternative_id

canonical_length

alternative_length

canonical_start

canonical_end

type

originalSEQ

variationSEQ

alternative_start

alternative_end

P05019

IGF1

P05019-1

P05019-2

195

153

135

195

Substitution

YQPPSTNKNTKSQRRKGWPKTHPGGEQKEGTEASLQIRGKKKEQRREIGSRNAECRGKKGK

EVHLKNASRGSAGNKNYRM

135

153

P05019

IGF1

P05019-1

P05019-3

195

137

Substitution

MGKISSLPTQLFKCCFCDFLK

MITPT

P05019

IGF1

P05019-1

P05019-3

195

137

135

195

Substitution

YQPPSTNKNTKSQRRKGWPKTHPGGEQKEGTEASLQIRGKKKEQRREIGSRNAECRGKKGK

EVHLKNASRGSAGNKNYRM

119

137

P05019

IGF1

P05019-1

P05019-4

195

158

152

195

Substitution

WPKTHPGGEQKEGTEASLQIRGKKKEQRREIGSRNAECRGKKGK

STFEERK

152

158

Multiple sequence alignment of our canonical and alternatively spliced IGF1

Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of IGF1

UniProt-id	ENSG	ENST	ENSP
P05019-1	ENSG00000017427.17	ENST00000307046.8	ENSP00000302665.8
P05019-2	ENSG00000017427.17	ENST00000337514.11	ENSP00000337612.7
P05019-2	ENSG00000017427.17	ENST00000644491.1	ENSP00000494228.1
P05019-3	ENSG00000017427.17	ENST00000424202.6	ENSP00000416811.2
P05019-4	ENSG00000017427.17	ENST00000392904.5	ENSP00000376637.1
P05019-4	ENSG00000017427.17	ENST00000392905.7	ENSP00000376638.3

UniProt-id	NM ID	NP ID
P05019-1	NM_001111285.2	NP_001104755.1
P05019-2	NM_000618.4	NP_000609.1
P05019-3	NM_001111284.1	NP_001104754.1

Amino acid sequences of our canonical and alternatively spliced IGF1

accession_id	Protein sequence
P05019-1	MGKISSLPTQLFKCCFCDFLKVKMHTMSSSHLFYLALCLLTFTSSATAGPETLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTG IVDECCFRSCDLRRLEMYCAPLKPAKSARSVRAQRHTDMPKTQKYQPPSTNKNTKSQRRKGWPKTHPGGEQKEGTEASLQIRGKKKEQRR
P05019-2	MGKISSLPTQLFKCCFCDFLKVKMHTMSSSHLFYLALCLLTFTSSATAGPETLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTG
P05019-3	MITPTVKMHTMSSSHLFYLALCLLTFTSSATAGPETLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTGIVDECCFRSCDLRRLE
P05019-4	MGKISSLPTQLFKCCFCDFLKVKMHTMSSSHLFYLALCLLTFTSSATAGPETLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTG

Protein Functional Features

Main function of this protein. (from UniProt)

IGF1 (go to UniProt):P05019

Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at
download page
* Minus value of BPloci means that the break pointn is located before the CDS.

- Retained protein feature among the 13 regional features.

Accession_id	Subsection	Start	End	Funcitonal feature	Splicing information
P05019	Region	119	195	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=135;End=195
P05019	Region	119	195	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=135;End=195
P05019	Region	119	195	Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=152;End=195
P05019	Compositional bias	130	146	Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=135;End=195
P05019	Compositional bias	130	146	Note=Polar residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=135;End=195
P05019	Compositional bias	153	195	Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=135;End=195
P05019	Compositional bias	153	195	Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=135;End=195
P05019	Compositional bias	153	195	Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256\|SAM:MobiDB-lite	Type=Substitution;Start=152;End=195

Gene Isoform Structures and Expression Levels for IGF1

Gene structures of our canonical and alternative spliced genes of IGF1
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

Expression levels of gene isoforms across GTEx.

Expression levels of gene isoforms across TCGA.

Protein Structures

PDB and CIF files of the predicted protein structures
* Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format.

3D view using mol* of P05019-1

3D view using mol* of P05019-2

3D view using mol* of P05019-3

3D view using mol* of P05019-4

pLDDT Score Distribution

pLDDT score distribution of the predicted protein structures from AlphaFold2
* AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100.

pLDDT distribution across the protein length of P05019-1

pLDDT distribution across the protein length of P05019-2

pLDDT distribution across the protein length of P05019-3

pLDDT distribution across the protein length of P05019-4

Ramachandran Plot of Protein Structures

Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide.

Ramachandran plot of P05019-1

Ramachandran plot of P05019-2

Potential Active Site Information

The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite.

UniProt-id	Site score	Size	D score	Volume	Exposure	Enclosure	Contact	Phobic	Philic	Balance	Don/Acc	Residues
P05019-1	0.974	95	1.009	314.188	0.642	0.65	0.918	0.859	0.913	0.941	1.694	38,41,42,45,46,48,49,50,51,52,53,54,57,58,60,61,64 ,65,95,96,97,98,99,100,102,105
P05019-2	0.906	65	0.939	279.202	0.727	0.66	0.763	0.696	0.659	1.056	3.011	45,46,48,49,50,51,52,53,57,58,61,91,95,96,97,98,99 ,100,105
P05019-3	1.002	102	1.046	387.247	0.611	0.653	0.826	0.473	0.878	0.539	1.754	29,32,33,34,35,36,37,41,42,44,45,75,79,80,81,83,84 ,89
P05019-4	1.031	160	1.087	398.909	0.502	0.669	0.88	0.596	0.78	0.763	1.682	42,45,46,47,48,49,50,51,52,53,57,58,60,61,62,65,91 ,95,96,97,98,99,100,102,105

Protein Structure and Feature Comparision

Protein Structure Comparision Using Template Modeling Scores (TM-score).

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green)

3D view using mol* of P05019-1_P05019-1_1h02_B.pdb

Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P05019-1_1h02_B_P05019-2.pdb

3D view using mol* of P05019-1_1h02_B_P05019-3.pdb

3D view using mol* of P05019-1_1h02_B_P05019-4.pdb

Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green)

3D view using mol* of P05019-1_P05019-2.pdb

3D view using mol* of P05019-1_P05019-3.pdb

3D view using mol* of P05019-1_P05019-4.pdb

Protein Feature Comparison of the protein sequendary structures among the protiens.

./stats/secondary_structure/figure/P05019-1_vs_P05019-2.png

./stats/secondary_structure/figure/P05019-1_vs_P05019-3.png

./stats/secondary_structure/figure/P05019-1_vs_P05019-4.png

Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens.

./stats/relative_asa/P05019-1_vs_P05019-2.png

./stats/relative_asa/P05019-1_vs_P05019-3.png

./stats/relative_asa/P05019-1_vs_P05019-4.png

Protein-Protein Interaction

Interactors from UniProt.

Accession_id

Subsection

Start

End

Funcitonal feature

Splicing information

Interactors from STRING.

Gene name

Interactors

Related Drugs to IGF1

Drugs targeting this gene/protein.
(DrugBank)

UniProt accession	Gene name	DrugBank ID	Drug name	Drug group	Actions
P05019	IGF1	DB01890	N,N-Bis(3-(D-gluconamido)propyl)deoxycholamide	experimental
P05019	IGF1	DB02643	N-Dodecyl-N,N-Dimethyl-3-Ammonio-1-Propanesulfonate	experimental

Related Diseases to IGF1

Previous studies relating to the alternative splicing of IGF1 and disease information from the MeSH term (PubMed)

Gene	PMID	Title	Abstract	MeSH ID	MeSH term
IGF1	7720641	An alternatively spliced human insulin-like growth factor-I transcript with hepatic tissue expression that diverts away from the mitogenic IBE1 peptide.	An alternatively spliced transcript of the human insulin-like growth factor-I (IGF-I) gene is described. The transcript was identified in human liver RNA by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. It contained IGF-I exons 3 and 4, 49 basepairs of exon 5, then exon 6 (exon 4-5-6). The 5'-donor site at the exon 5-6 junction was a cryptic 5'-donor splice site (IGF633). The 3'-acceptor site of the splice was the usual intron-exon 6 junction. A second pair of primers across the exon 5-exon 6 junction was used to confirm the presence of the transcript by reverse transcriptase-polymerase chain reaction. Cloning and sequencing this second fragment confirmed the presence of this splice in human liver. The exon 4-5-6 transcript was quantified at about 10% relative to the exon 4-6 transcript in human livers (n = 7 subjects), but was not detected in other tissues. The exon 4-5-6 transcript was found in cultured human hepatoma HepG2 cells and increased, relative to exon 4-6 transcripts, in response to GH, but not in cultured human lymphoblast IM-9 cells. The exon 4-5-6 splice predicts a prepro-IGF-I of 158 amino acid residues, with an E-peptide sequence of 24 residues (Ec). The deduced Ec peptide sequence is 73% homologous to the rat Eb-peptide sequence. The predicted final residues of the Ec peptide are frameshifted exon 6 codons ending in an in-frame stop codon. The predicted peptide sequences of Ec and Eb differ at the cleavage site of the Eb-peptide fragment (IBE1), which has been shown to have mitogenic activity. These data suggest that 1) the exon 4-5-6 splice has hepatic tissue expression and occurs by the use of a cryptic 5'-donor consensus splice site (IGF633) in exon 5; 2) exon 4-5-6 can be hormonally regulated in cultured human HepG2 cells; 3) exon 4-5-6 is the human counterpart of the rat IGF-IEb, because the complementary DNA and predicted sequences are homologous; and 4) the production of IBE1 is potentially regulated by alternative splicing.	D006528	Carcinoma, Hepatocellular
IGF1	7720641	An alternatively spliced human insulin-like growth factor-I transcript with hepatic tissue expression that diverts away from the mitogenic IBE1 peptide.	An alternatively spliced transcript of the human insulin-like growth factor-I (IGF-I) gene is described. The transcript was identified in human liver RNA by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. It contained IGF-I exons 3 and 4, 49 basepairs of exon 5, then exon 6 (exon 4-5-6). The 5'-donor site at the exon 5-6 junction was a cryptic 5'-donor splice site (IGF633). The 3'-acceptor site of the splice was the usual intron-exon 6 junction. A second pair of primers across the exon 5-exon 6 junction was used to confirm the presence of the transcript by reverse transcriptase-polymerase chain reaction. Cloning and sequencing this second fragment confirmed the presence of this splice in human liver. The exon 4-5-6 transcript was quantified at about 10% relative to the exon 4-6 transcript in human livers (n = 7 subjects), but was not detected in other tissues. The exon 4-5-6 transcript was found in cultured human hepatoma HepG2 cells and increased, relative to exon 4-6 transcripts, in response to GH, but not in cultured human lymphoblast IM-9 cells. The exon 4-5-6 splice predicts a prepro-IGF-I of 158 amino acid residues, with an E-peptide sequence of 24 residues (Ec). The deduced Ec peptide sequence is 73% homologous to the rat Eb-peptide sequence. The predicted final residues of the Ec peptide are frameshifted exon 6 codons ending in an in-frame stop codon. The predicted peptide sequences of Ec and Eb differ at the cleavage site of the Eb-peptide fragment (IBE1), which has been shown to have mitogenic activity. These data suggest that 1) the exon 4-5-6 splice has hepatic tissue expression and occurs by the use of a cryptic 5'-donor consensus splice site (IGF633) in exon 5; 2) exon 4-5-6 can be hormonally regulated in cultured human HepG2 cells; 3) exon 4-5-6 is the human counterpart of the rat IGF-IEb, because the complementary DNA and predicted sequences are homologous; and 4) the production of IBE1 is potentially regulated by alternative splicing.	D008113	Liver Neoplasms
IGF1	8495408	Characterization of insulin-like growth factor 1 in human primary brain tumors.	Insulin-like growth factor 1 (IGF-1) is involved in the regulation of brain development and has been suggested as an autocrine stimulator of brain tumor cell proliferation. This study demonstrates the expression of IGF-1 in tumor tissue from human gliomas and one esthesioneuroblastoma. Using immunohistochemistry, expression of an IGF-1-like peptide was localized in tumor cells of 6 of the 9 gliomas examined as well as the esthesioneuroblastoma. From one anaplastic oligodendroglioma (which showed strong IGF-1 immunostaining) the IGF-1 transcripts were characterized after isolation of mRNA followed by amplification using the reverse transcriptase-polymerase chain reaction. Two IGF-1 complementary DNAs resulting from alternative splicing of the IGF-1 primary transcript were identified. These transcripts encode two different precursor proteins which correspond to Ea IGF-1 and Eb IGF-1. The significance of IGF-1 alternative mRNA splicing pathways remains to be determined.	D001932	Brain Neoplasms
IGF1	8495408	Characterization of insulin-like growth factor 1 in human primary brain tumors.	Insulin-like growth factor 1 (IGF-1) is involved in the regulation of brain development and has been suggested as an autocrine stimulator of brain tumor cell proliferation. This study demonstrates the expression of IGF-1 in tumor tissue from human gliomas and one esthesioneuroblastoma. Using immunohistochemistry, expression of an IGF-1-like peptide was localized in tumor cells of 6 of the 9 gliomas examined as well as the esthesioneuroblastoma. From one anaplastic oligodendroglioma (which showed strong IGF-1 immunostaining) the IGF-1 transcripts were characterized after isolation of mRNA followed by amplification using the reverse transcriptase-polymerase chain reaction. Two IGF-1 complementary DNAs resulting from alternative splicing of the IGF-1 primary transcript were identified. These transcripts encode two different precursor proteins which correspond to Ea IGF-1 and Eb IGF-1. The significance of IGF-1 alternative mRNA splicing pathways remains to be determined.	D005910	Glioma
IGF1	8495408	Characterization of insulin-like growth factor 1 in human primary brain tumors.	Insulin-like growth factor 1 (IGF-1) is involved in the regulation of brain development and has been suggested as an autocrine stimulator of brain tumor cell proliferation. This study demonstrates the expression of IGF-1 in tumor tissue from human gliomas and one esthesioneuroblastoma. Using immunohistochemistry, expression of an IGF-1-like peptide was localized in tumor cells of 6 of the 9 gliomas examined as well as the esthesioneuroblastoma. From one anaplastic oligodendroglioma (which showed strong IGF-1 immunostaining) the IGF-1 transcripts were characterized after isolation of mRNA followed by amplification using the reverse transcriptase-polymerase chain reaction. Two IGF-1 complementary DNAs resulting from alternative splicing of the IGF-1 primary transcript were identified. These transcripts encode two different precursor proteins which correspond to Ea IGF-1 and Eb IGF-1. The significance of IGF-1 alternative mRNA splicing pathways remains to be determined.	D018241	Neuroectodermal Tumors, Primitive, Peripheral
IGF1	20403997	Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer.	Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis, modifies the effect of statins on serum cholesterol levels. Long-term use of statins is associated with a reduced risk of colorectal cancer (CRC) in some, but not all, studies. We genotyped variants in 40 candidate genes important for cholesterol synthesis and metabolism in a population-based case-control study of CRC involving 2,138 incident cases and 2,049 population-based controls. We identified a single-nucleotide polymorphism in the HMGCR gene that significantly modified the protective association between statins and CRC risk. Compared with nonusers, the unadjusted odds ratio of CRC among statin users with the A/A genotype of rs12654264 in HMGCR was 0.3 (95% confidence interval, 0.18-0.51) and among statin users with the T/T genotype was 0.66 (95% confidence interval, 0.41-1.06; P-interaction = 0.0012). This genetic variant (A/A genotype of rs12654264) also was associated with lower serum levels of low-density lipoprotein among all cases and controls. In colon cancer cell lines, the reduction in cholesterol levels after statin treatment was substantially stronger in cells carrying the A/A genotype, and this difference was related to alternative splicing involving the HMGCR statin-binding domain. We anticipate that these data may advance the development of personalized statin use for reducing the risk of cancer as well as cardiovascular disease among the approximately 25 million people currently using statins worldwide.	D015179	Colorectal Neoplasms
IGF1	23712705	The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction.	Insulin-like growth factor-1 (IGF-1) isoforms are expressed via alternative splicing. Expression of the minor isoform IGF-1Eb [also known as mechano-growth factor (MGF)] is responsive to cell stress. Since IGF-1 isoforms differ in their E-domain regions, we are interested in determining the biological function of the MGF E-domain. To do so, a synthetic peptide analog was used to gain mechanistic insight into the actions of the E-domain. Treatment of H9c2 cells indicated a rapid cellular uptake mechanism that did not involve IGF-1 receptor activation but resulted in a nuclear localization. Peptide treatment inhibited the intrinsic apoptotic pathway in H9c2 cells subjected to cell stress with sorbitol by preventing the collapse of the mitochondrial membrane potential and inhibition of caspase-3 activation. Therefore, we administered the peptide at the time of myocardial infarction (MI) in mice. At 2 weeks post-MI cardiac function, gene expression and cell death were assayed. A significant decline in both systolic and diastolic function was evident in untreated mice based on PV loop analysis. Delivery of the E-peptide ameliorated the decline in function and resulted in significant preservation of cardiac contractility. Associated with these changes were an inhibition of pathologic hypertrophy and significantly fewer apoptotic nuclei in the viable myocardium of E-peptide-treated mice post-MI. We conclude that administration of the MGF E-domain peptide may provide a means of modulating local tissue IGF-1 autocrine/paracrine actions to preserve cardiac function, prevent cell death, and pathologic remodeling in the heart.	D006332	Cardiomegaly
IGF1	23712705	The E-domain region of mechano-growth factor inhibits cellular apoptosis and preserves cardiac function during myocardial infarction.	Insulin-like growth factor-1 (IGF-1) isoforms are expressed via alternative splicing. Expression of the minor isoform IGF-1Eb [also known as mechano-growth factor (MGF)] is responsive to cell stress. Since IGF-1 isoforms differ in their E-domain regions, we are interested in determining the biological function of the MGF E-domain. To do so, a synthetic peptide analog was used to gain mechanistic insight into the actions of the E-domain. Treatment of H9c2 cells indicated a rapid cellular uptake mechanism that did not involve IGF-1 receptor activation but resulted in a nuclear localization. Peptide treatment inhibited the intrinsic apoptotic pathway in H9c2 cells subjected to cell stress with sorbitol by preventing the collapse of the mitochondrial membrane potential and inhibition of caspase-3 activation. Therefore, we administered the peptide at the time of myocardial infarction (MI) in mice. At 2 weeks post-MI cardiac function, gene expression and cell death were assayed. A significant decline in both systolic and diastolic function was evident in untreated mice based on PV loop analysis. Delivery of the E-peptide ameliorated the decline in function and resulted in significant preservation of cardiac contractility. Associated with these changes were an inhibition of pathologic hypertrophy and significantly fewer apoptotic nuclei in the viable myocardium of E-peptide-treated mice post-MI. We conclude that administration of the MGF E-domain peptide may provide a means of modulating local tissue IGF-1 autocrine/paracrine actions to preserve cardiac function, prevent cell death, and pathologic remodeling in the heart.	D009203	Myocardial Infarction

Clinically important variants in IGF1

(ClinVar, 04/20/2024)

accession_id

uniprot_id

gene_name

Type

Variant

Clinical_significance