Protein:INSR |
Protein Summary |
 Gene summary |
| Gene name: INSR | ASpdb.0 ID: 3643 | Gene | Gene symbol | INSR | Gene ID | 3643 |
| Gene name | insulin receptor |
| Synonyms | CD220|HHF5 |
| Cytomap | 19p13.2 |
| Type of gene | protein-coding |
| Description | insulin receptorIR |
| Modification date | 20240413 |
| UniProtAcc | P06213 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | INSR | GO:0001934 | positive regulation of protein phosphorylation | 7556070 |
| Gene | INSR | GO:0002092 | positive regulation of receptor internalization | 25401701 |
| Gene | INSR | GO:0004713 | protein tyrosine kinase activity | 8496180|38056462 |
| Gene | INSR | GO:0005009 | insulin receptor activity | 6849137|8440175|38056462 |
| Gene | INSR | GO:0005159 | insulin-like growth factor receptor binding | 8452530 |
| Gene | INSR | GO:0005524 | ATP binding | 6849137 |
| Gene | INSR | GO:0005525 | GTP binding | 9092559 |
| Gene | INSR | GO:0005635 | nuclear envelope | 19406747 |
| Gene | INSR | GO:0005886 | plasma membrane | 9092559|23137377 |
| Gene | INSR | GO:0005899 | insulin receptor complex | 1898103|19406747 |
| Gene | INSR | GO:0005901 | caveola | 15182363 |
| Gene | INSR | GO:0007186 | G protein-coupled receptor signaling pathway | 9092559 |
| Gene | INSR | GO:0008284 | positive regulation of cell population proliferation | 17925406 |
| Gene | INSR | GO:0008286 | insulin receptor signaling pathway | 6849137|8440175|20455999|38056462 |
| Gene | INSR | GO:0016020 | membrane | 8452530 |
| Gene | INSR | GO:0018108 | peptidyl-tyrosine phosphorylation | 8496180 |
| Gene | INSR | GO:0031981 | nuclear lumen | 19406747 |
| Gene | INSR | GO:0032148 | activation of protein kinase B activity | 7556070 |
| Gene | INSR | GO:0032869 | cellular response to insulin stimulus | 8440175 |
| Gene | INSR | GO:0043235 | receptor complex | 23382219 |
| Gene | INSR | GO:0043410 | positive regulation of MAPK cascade | 20455999 |
| Gene | INSR | GO:0043559 | insulin binding | 8440175 |
| Gene | INSR | GO:0045725 | positive regulation of glycogen biosynthetic process | 17925406 |
| Gene | INSR | GO:0046326 | positive regulation of glucose import | 3518947 |
| Gene | INSR | GO:0046777 | protein autophosphorylation | 6849137|8496180 |
| Gene | INSR | GO:0060267 | positive regulation of respiratory burst | 9092559 |
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 |
| P06213-1 | P06213-1_6pxv_A.pdb | 6PXV | EM | 3.2 | A | 28 | 949 |
| 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 |
| P06213 | INSR | P06213-1 | P06213-2 | 1382 | 1370 | 745 | 756 | Deletion | none | none | 744 | 744 |
| Multiple sequence alignment of our canonical and alternatively spliced INSR |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of INSR |
| UniProt-id | ENSG | ENST | ENSP |
| P06213-1 | ENSG00000171105.14 | ENST00000302850.10 | ENSP00000303830.4 |
| P06213-2 | ENSG00000171105.14 | ENST00000341500.9 | ENSP00000342838.4 |
| UniProt-id | NM ID | NP ID |
| P06213-1 | NM_000208.3 | NP_000199.2 |
| P06213-2 | NM_001079817.2 | NP_001073285.1 |
| Amino acid sequences of our canonical and alternatively spliced INSR |
| accession_id | Protein sequence |
| P06213-1 | MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLL FRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNE ECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECLGNCSQPDDPTKCVACRNFYLDGRCVETCPP PYYHFQDWRCVNFSFCQDLHHKCKNSRRQGCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGC TVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETLEIGNYSFYALDNQNLRQLWDWSKHNLTITQ GKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQ NVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPIS VSNSSSQIILKWKPPSDPNGNITHYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQIL KELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVIS GLRHFTGYRIELQACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCV SRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPLGP LYASSNPEYLSASDVFPCSVYVPDEWEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKG FTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAARNCMVAHD FTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDN CPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLG |
| P06213-2 | MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLL FRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNE ECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECLGNCSQPDDPTKCVACRNFYLDGRCVETCPP PYYHFQDWRCVNFSFCQDLHHKCKNSRRQGCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGC TVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETLEIGNYSFYALDNQNLRQLWDWSKHNLTITQ GKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQ NVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPIS VSNSSSQIILKWKPPSDPNGNITHYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQIL KELEESSFRKTFEDYLHNVVFVPRPSRKRRSLGDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIEL QACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCR LRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSA SDVFPCSVYVPDEWEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKGFTCHHVVRLLGV VSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTR DIYETDYYRKGGKGLLPVRWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDNCPERVTDLMRMC WQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYT |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| INSR (go to UniProt):P06213 |
| 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 * 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 |
| P06213 | Topological domain | 28 | 758 | Note=Extracellular;Ontology_term=ECO:0000305;evidence=ECO:0000305 | Type=Deletion;Start=745;End=756 |
| P06213 | Region | 746 | 766 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=745;End=756 |
Gene Isoform Structures and Expression Levels for INSR |
| Gene structures of our canonical and alternative spliced genes of INSR * 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. |
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| Expression levels of gene isoforms across TCGA. |
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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 P06213-1 |
| 3D view using mol* of P06213-2 |
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 P06213-1 |
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| pLDDT distribution across the protein length of P06213-2 |
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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 P06213-1 |
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| Ramachandran plot of P06213-2 |
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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 |
| P06213-1 | 1.101 | 138 | 1.046 | 373.184 | 0.441 | 0.848 | 1.111 | 0.927 | 1.236 | 0.75 | 0.841 | 1027,1029,1030,1031,1032,1033,1037,1055,1057,1074, 1078,1087,1103,1105,1106,1107,1109,1110,1112,1159, 1163,1164,1166,1176,1177,1178,1181,1182,1183,1184, 1185,1189 |
| P06213-2 | 1.038 | 333 | 1.086 | 1019.396 | 0.642 | 0.691 | 0.834 | 0.661 | 0.823 | 0.803 | 1.054 | 117,118,143,169,170,171,349,350,351,371,372,373,37 4,377,399,401,433,434,459,460,462,463,464,467,470, 477,479,480,481,483,484,486,487,489,490,491,492,49 3,494,495,496,497,498,531,533,544,547,548,549,550, 551,552,554,556,558,592,594,595,596,597,599,600,60 3,604,605,606,607,717,720,721,723,724,725,727,728 |
Protein Structure and Feature Comparision |
| Protein Structure Comparision Using Template Modeling Scores (TM-score). |
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| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green) |
| 3D view using mol* of P06213-1_P06213-1_6pxv_A.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P06213-1_6pxv_A_P06213-2.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P06213-1_P06213-2.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/P06213-1_vs_P06213-2.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/P06213-1_vs_P06213-2.png |
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Protein-Protein Interaction |
| Interactors from UniProt. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Interactors from STRING. |
| Gene name | Interactors |
Related Drugs to INSR |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
| P06213 | INSR | DB09456 | Insulin beef | approved | agonist |
| P06213 | INSR | DB08513 | [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID | experimental | |
| P06213 | INSR | DB15399 | BMS-754807 | investigational | inhibitor |
| P06213 | INSR | DB06075 | Linsitinib | investigational | inhibitor |
| P06213 | INSR | DB03909 | Adenosine-5'-[Beta, Gamma-Methylene]Triphosphate | experimental | |
| P06213 | INSR | DB11568 | Insulin tregopil | investigational | agonist |
| P06213 | INSR | DB00071 | Insulin pork | approved | binder |
| P06213 | INSR | DB00046 | Insulin lispro | approved | agonist |
| P06213 | INSR | DB12267 | Brigatinib | approved, investigational | binding |
| P06213 | INSR | DB11567 | Insulin peglispro | investigational | |
| P06213 | INSR | DB05115 | NN344 | investigational | |
| P06213 | INSR | DB12010 | Fostamatinib | approved, investigational | inhibitor |
| P06213 | INSR | DB01309 | Insulin glulisine | approved | agonist |
| P06213 | INSR | DB05120 | AT1391 | investigational | |
| P06213 | INSR | DB09129 | Chromic chloride | approved | activator |
| P06213 | INSR | DB16637 | KW-2450 free base | experimental | inhibitor |
| P06213 | INSR | DB11564 | Insulin argine | experimental | agonist |
| P06213 | INSR | DB09564 | Insulin degludec | approved | agonist |
| P06213 | INSR | DB01277 | Mecasermin | approved, investigational | |
| P06213 | INSR | DB00047 | Insulin glargine | approved | agonist |
| P06213 | INSR | DB14751 | Mecasermin rinfabate | approved | |
| P06213 | INSR | DB01306 | Insulin aspart | approved | agonist |
| P06213 | INSR | DB00030 | Insulin human | approved, investigational | agonist |
| P06213 | INSR | DB01307 | Insulin detemir | approved | agonist |
Related Diseases to INSR |
| Previous studies relating to the alternative splicing of INSR and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| INSR | 2538124 | Alternative splicing of human insulin receptor messenger RNA. | The polymerase chain reaction has been used to examine alternative splicing of human insulin receptor (hINSR) mRNA. Alternative splicing of a 36 base pair exon, exon 11, generates hINSR transcripts encoding receptor isoforms which differ in sequence at the C-terminal end of the insulin-binding alpha-subunit. This process appears to be tissue-specific and, in addition, may be developmentally regulated. | D006528 | Carcinoma, Hepatocellular |
| INSR | 2538124 | Alternative splicing of human insulin receptor messenger RNA. | The polymerase chain reaction has been used to examine alternative splicing of human insulin receptor (hINSR) mRNA. Alternative splicing of a 36 base pair exon, exon 11, generates hINSR transcripts encoding receptor isoforms which differ in sequence at the C-terminal end of the insulin-binding alpha-subunit. This process appears to be tissue-specific and, in addition, may be developmentally regulated. | D008113 | Liver Neoplasms |
| INSR | 15114529 | Insulin receptor splicing alteration in myotonic dystrophy type 2. | Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3' untranslated region of the DMPK gene on chromosome 19 (dystrophia myotonica type 1 [DM1]), or an untranslated CCTG tetranucleotide repeat expansion in intron 1 of the ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 [DM2]). RNA-binding proteins adhere to transcripts of the repeat expansions that accumulate in the nucleus, and a trans-dominant dysregulation of pre-mRNA alternative splicing has been demonstrated for several genes. In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. We now demonstrate that comparable splicing abnormalities occur in DM2 muscle prior to the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions. | D007333 | Insulin Resistance |
| INSR | 15114529 | Insulin receptor splicing alteration in myotonic dystrophy type 2. | Myotonic dystrophy (DM) is caused by either an untranslated CTG expansion in the 3' untranslated region of the DMPK gene on chromosome 19 (dystrophia myotonica type 1 [DM1]), or an untranslated CCTG tetranucleotide repeat expansion in intron 1 of the ZNF9 gene on chromosome 3 (dystrophia myotonica type 2 [DM2]). RNA-binding proteins adhere to transcripts of the repeat expansions that accumulate in the nucleus, and a trans-dominant dysregulation of pre-mRNA alternative splicing has been demonstrated for several genes. In muscle from patients with DM1, altered insulin-receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the DM phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of the disease. We now demonstrate that comparable splicing abnormalities occur in DM2 muscle prior to the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions. | D009223 | Myotonic Dystrophy |
| INSR | 19326042 | Comparative transcriptional and biochemical studies in muscle of myotonic dystrophies (DM1 and DM2). | Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (proximal muscular myopaty/DM2) are caused by similar dynamic mutations at two distinct genetic loci. The two diseases also lead to similar phenotypes but different clinical severity. Dysregulation of alternative splicing has been suggested as the common pathogenic mechanism. Here, we investigate the molecular differences between DM1 and DM2 using reverse transcriptase-polymerase chain reaction of troponin T (TnT) and the insulin receptor (IR), as well as immunoblotting of TnT in muscle biopsies from DM1 and DM2 patients. We found that: (a) slow TnT was encoded by two different transcripts in significantly different ratios in DM1 and DM2 muscles; (b) DM2 muscles exhibited a higher degree of alternative splicing dysregulation for fast TnT transcripts when compared to DM1 muscles; (c) the distribution of TnT proteins was significantly skewed towards higher molecular weight species in both diseases; (d) the RNA for the insulin-independent IR-A isoform was significantly increased and appeared related to the fibre-type composition in the majority of the cases examined. On the whole, these data should give a better insight on pathogenesis of DM1 and DM2. | D020967 | Myotonic Disorders |
| INSR | 19326042 | Comparative transcriptional and biochemical studies in muscle of myotonic dystrophies (DM1 and DM2). | Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (proximal muscular myopaty/DM2) are caused by similar dynamic mutations at two distinct genetic loci. The two diseases also lead to similar phenotypes but different clinical severity. Dysregulation of alternative splicing has been suggested as the common pathogenic mechanism. Here, we investigate the molecular differences between DM1 and DM2 using reverse transcriptase-polymerase chain reaction of troponin T (TnT) and the insulin receptor (IR), as well as immunoblotting of TnT in muscle biopsies from DM1 and DM2 patients. We found that: (a) slow TnT was encoded by two different transcripts in significantly different ratios in DM1 and DM2 muscles; (b) DM2 muscles exhibited a higher degree of alternative splicing dysregulation for fast TnT transcripts when compared to DM1 muscles; (c) the distribution of TnT proteins was significantly skewed towards higher molecular weight species in both diseases; (d) the RNA for the insulin-independent IR-A isoform was significantly increased and appeared related to the fibre-type composition in the majority of the cases examined. On the whole, these data should give a better insight on pathogenesis of DM1 and DM2. | D009223 | Myotonic Dystrophy |
| INSR | 23633480 | Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. | Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. | D006528 | Carcinoma, Hepatocellular |
| INSR | 23633480 | Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. | Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. | D002471 | Cell Transformation, Neoplastic |
| INSR | 23633480 | Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. | Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC. | D008114 | Liver Neoplasms, Experimental |
| INSR | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D004392 | Dwarfism |
| INSR | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D006130 | Growth Disorders |
| INSR | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D009123 | Muscle Hypotonia |
Clinically important variants in INSR |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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