Tclin INSR Insulin receptor

Protein Summary

Description

Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. This gene encodes a member of the receptor tyrosine kinase family of proteins. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form a heterotetrameric receptor. Binding of insulin or other ligands to this receptor activates the insulin signaling pathway, which regulates glucose uptake and release, as well as the synthesis and storage of carbohydrates, lipids and protein. Mutations in this gene underlie the inherited severe insulin resistance syndromes including type A insulin resistance syndrome, Donohue syndrome and Rabson-Mendenhall syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

Uniprot Accession IDs

• P06213
• Q17RW0
• Q59H98
• Q9UCB7
• Q9UCB8
• Q9UCB9
• IR

Gene Name

• INSR

Ensembl ID

• ENST00000302850
• ENSP00000303830
• ENSG00000171105
• ENST00000341500
• ENSP00000342838

Symbol

• HHF5
• CD220

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	1
biological term	1
hub protein	1
molecular function	1
protein domain	1

Protein Classes

DTO Classes

Protein / Kinase / Protein Kinase / Tk Group / Insr Family / Insulin Receptor

IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 439.19   (req: < 5)

Gene RIFs: 295   (req: <= 3)

Antibodies: 1926   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 439.19   (req: >= 5)

Gene RIFs: 295   (req: > 3)

Antibodies: 1926   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 65

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 89

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drugs: 9

Protein Sequence and Structure

Residue Counts

Protein Sequence

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Expression Data (0 Tissues)

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No expression data found

Related Tools

ProKinO

The ProKinO is a protein kinase-specific ontology, which provides a controlled vocabulary of terms, their hierarchy, and relationships unifying sequence, structure, function, mutation and pathway information on kinases.

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Target Illumination GWAS Analytics (TIGA)

TIGA scores and ranks GWAS discovered associations according to the quantity and quality of the evidence supporting the association.

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GENEVA

GENEVA (GENe Expression Variance Analysis) allows you to identify RNA-sequencing datasets from the Gene Expression Omnibus (GEO) that contain conditions modulating a gene or a gene signature.

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GlyGen

GlyGen is a data integration and dissemination project for carbohydrate and glycoconjugate related data.

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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Approved Drugs (9)

Explore Approved Drugs

1 – 9 of 9

nintedanib

INSRTclin Kinase

INHIBITOR pIC50 : 7.42

ceritinib

INSRTclin Kinase

INHIBITOR pIC50 : 9.7

insulin glargine

INSRTclin Kinase

AGONIST :

insulin degludec

INSRTclin Kinase

AGONIST :

insulin aspart

INSRTclin Kinase

AGONIST :

insulin detemir

INSRTclin Kinase

AGONIST :

insulin lispro

INSRTclin Kinase

AGONIST :

insulin human

INSRTclin Kinase

AGONIST :

insulin glulisine

INSRTclin Kinase

AGONIST :

Active Ligands (89)

Explore Active Ligands

1 – 10 of 89

staurosporine

INSRTclin Kinase

pKd : 7.89

SID103905531

INSRTclin Kinase

pKi : 9.5

TAE-684

INSRTclin Kinase

pKi : 8.5

SID103904595

INSRTclin Kinase

pKi : 8.2

PF-03814735

INSRTclin Kinase

pKi : 7.9

SID103904326

INSRTclin Kinase

pKi : 8.4

dovitinib

INSRTclin Kinase

pKd : 7.57

SID103904418

INSRTclin Kinase

pKi : 8.6

BMS-536924

INSRTclin Kinase

pKi : 7.9

NVP-TAE 226

INSRTclin Kinase

pKi : 8.4

Protein-Protein Interactions (319)

Explore Interacting Targets

1 – 10 of 319

• See Interactions on String-DB

UNC5CL

Tbio

Novelty:  0.11511991

p_int:  0.999877875

p_ni:  0.000122125

Score:  0.188

Data Source:  BioPlex,STRINGDB

FAM19A4

Tbio

Novelty:  0.04305684

p_int:  0.993951292

p_ni:  0.006048708

Data Source:  BioPlex

HYOU1

Tbio

Novelty:  0.00833649

p_int:  0.992681225

p_ni:  0.007318776

Data Source:  BioPlex

SCGB1D1

Tbio

Novelty:  0.04199997

p_int:  0.992418197

p_ni:  0.007581803

Data Source:  BioPlex

PATE1

Tbio

Novelty:  0.0705075

p_int:  0.99146048

p_ni:  0.008539521

Data Source:  BioPlex

RLN1

Tbio

Novelty:  0.03992636

p_int:  0.976768249

p_ni:  0.023231752

Data Source:  BioPlex

IGF2

Tbio

Novelty:  0.00021277

p_int:  0.976580773

p_ni:  0.023419227

Score:  0.953

Data Source:  BioPlex,STRINGDB

DHFR2

Tbio

Family:  Enzyme

Novelty:  0.02374466

p_int:  0.957192758

p_ni:  0.042807243

Data Source:  BioPlex

PON2

Tbio

Family:  Enzyme

Novelty:  0.00414855

p_int:  0.952283291

p_ni:  0.047716709

Data Source:  BioPlex

PTPRK

Tbio

Family:  Enzyme

Novelty:  0.03149943

p_int:  0.94997313

p_ni:  0.05002687

Score:  0.285

Data Source:  BioPlex,STRINGDB

Nearest Tclin Targets

Nearest Tclin calculations are only available for targets with KEGG Pathway annotations.

Pathways (67)

Reactome (11)

KEGG (20)

PathwayCommons (15)

WikiPathways (21)

IRS activation (R-HSA-74713)

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1 – 5 of 11

Data Source	Name	Explore in Pharos	Explore in Source
Reactome	IRS activation	5 targets	R-HSA-74713
Reactome	Insulin receptor recycling	26 targets	R-HSA-77387
Reactome	Insulin receptor signalling cascade	54 targets	R-HSA-74751
Reactome	Intracellular signaling by second messengers	305 targets	R-HSA-9006925
Reactome	Negative regulation of the PI3K/AKT network	110 targets	R-HSA-199418

Name	Explore in Pharos	Explore in Source
IRS activation	5 targets	R-HSA-74713
Insulin receptor recycling	26 targets	R-HSA-77387
Insulin receptor signalling cascade	54 targets	R-HSA-74751
Intracellular signaling by second messengers	305 targets	R-HSA-9006925
Negative regulation of the PI3K/AKT network	110 targets	R-HSA-199418

Viral Interactions (0)

No viral interactions found

Gene Ontology Terms (79)

Functions (17)

Components (14)

Processes (48)

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1 – 10 of 17

GO Term	Evidence	Assigned by
ATP binding	Inferred from Direct Assay (IDA)	BHF-UCL
GTP binding	Inferred from Direct Assay (IDA)	BHF-UCL
insulin binding	Inferred from Direct Assay (IDA)	UniProtKB
insulin-activated receptor activity	Inferred from Direct Assay (IDA)	UniProtKB
insulin-like growth factor receptor binding	Inferred from Direct Assay (IDA)	BHF-UCL
protein tyrosine kinase activity	Inferred from Direct Assay (IDA)	BHF-UCL
amyloid-beta binding	Inferred from Physical Interaction (IPI)	ARUK-UCL
identical protein binding	Inferred from Physical Interaction (IPI)	IntAct
insulin receptor substrate binding	Inferred from Physical Interaction (IPI)	UniProtKB
insulin-like growth factor I binding	Inferred from Physical Interaction (IPI)	BHF-UCL

Disease Associations ()

No disease associations found

GWAS Traits (36)

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1 – 5 of 36

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
BMI-adjusted hip circumference	EFO_0008039	3	25	27		94.2
urate measurement	EFO_0004531	4	4	6		92.4
triglyceride measurement	EFO_0004530	6	6	7		92.1
BMI-adjusted waist-hip ratio	EFO_0007788	2	9	9		86.1
waist-hip ratio	EFO_0004343	3	10	11		85.4

• Explore on Target Illumination GWAS Analytics (TIGA)

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1 – 5 of 36

GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
BMI-adjusted hip circumference	EFO_0008039	27		94.2
urate measurement	EFO_0004531	6		92.4
triglyceride measurement	EFO_0004530	7		92.1
BMI-adjusted waist-hip ratio	EFO_0007788	9		86.1
waist-hip ratio	EFO_0004343	11		85.4

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Find similar targets by:

UniProt Keyword Find Similar Targets

No Header	No Header
3D-structure
Alternative splicing
ATP-binding
Carbohydrate metabolism
Cell membrane
Cleavage on pair of basic residues
Complete proteome
Diabetes mellitus
Direct protein sequencing
Disease mutation

GWAS Trait Find Similar Targets

No Header	No Header
Agents acting on the renin-angiotensin system use measurement
basophil count
Beta blocking agent use measurement
birth weight
blood urea nitrogen measurement
BMI-adjusted hip circumference
BMI-adjusted waist circumference
BMI-adjusted waist-hip ratio
body height
Calcium channel blocker use measurement

MGI Phenotype Find Similar Targets

No Header	No Header
adipose tissue phenotype
behavior/neurological phenotype
cellular phenotype
digestive/alimentary phenotype
endocrine/exocrine gland phenotype
growth/size/body region phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
liver/biliary system phenotype

IDG Resources

No IDG generated resources found

Orthologs (9)

1 – 5 of 9

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	insulin receptor	VGNC:11232	455649
Mouse	insulin receptor	MGI:96575	16337
Rat	insulin receptor	RGD:2917	24954
Dog	insulin receptor	VGNC:42043	484990
Horse	insulin receptor	VGNC:19083	100066248

Species	Name	OMA	EggNOG	Inparanoid
Chimp	insulin receptor
Mouse	insulin receptor
Rat	insulin receptor
Dog	insulin receptor
Horse	insulin receptor

Publication Statistics

PubMed Score 439.19

PubMed score by year

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PubTator Score 2952.35

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Patents

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Related Publications

Text Mined References (588)

GeneRif Annotations (295)

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PMID	Year	Title