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PsychedeliaDokholyan Laboratory
TargetOther named receptors

Insulin receptor

A named receptor outside the families above. The catch-all is explicit rather than silent: these are receptors, but they are not grouped.

Measurements
14
Compounds
7
Binding constants
7
Median pX
—

I · Identity

What this target is

Its function as UniProt states it, where in a cell the protein is found, and which cell types and tissues transcribe its gene.

Protein

INSR_HUMANINSRHomo sapiens

Insulin receptor

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. In adipocytes, inhibits lipolysis (By similarity)

Quoted from UniProt’s FUNCTION annotation for P06213 (reviewed). The superscript numbers are UniProt’s own PubMed citations, kept in the sentence and in order, each linking to the paper it names.

What it acts with

STRING’s highest-confidence human functional partners. The combined score mixes several kinds of evidence, so each channel is shown separately — a partner supported by experiment is a different claim from one supported only by text mining, and for a receptor this is where its coupling appears as evidence rather than as assertion.

PartnerCombinedExperimentDatabaseText mining
IRS10.9990.9900.9000.991
IRS20.9990.9650.9000.903
PTPN10.9990.9910.9000.760
INS0.9990.9830.9000.999
IGF10.9990.9660.9000.995
IGF1R0.9970.9270.9000.696
GRB140.9960.9780.0000.825
SH2B20.9950.9490.9000.215
SHC10.9940.7950.9000.751
IGF20.9910.1640.6500.971

Where it sits in the cell

  • Vesicles
  • Plasma membrane
  • Primary cilium transition zoneadditional
  • Centriolar satelliteadditional
  • Basal bodyadditional

Human Protein Atlas, by antibody immunofluorescence in cell lines — a different assay from the expression figures below, which are RNA.

UniProt, curated Cell membrane · Late endosome · Lysosome

Expression by cell type

Single cell type RNA, the 2 highest of those the Human Protein Atlas reports for this gene. Transcript, not protein, and a cell type rather than a tissue.

  • Pancreatic acinar cells1,376.5 nCPM
  • Peritubular myoid cells827.8 nCPM

II · Anatomy

Where the gene is transcribed

The same two atlases the compound plates use, asked about this gene alone. Brain on the left, peripheral and autonomic tissues on the right.

Brain

cerebral cortex — 6.7 nTPM, from INSRcerebellum — 11.6 nTPM, from INSRhippocampal formation — 7.3 nTPM, from INSRamygdala — 6.0 nTPM, from INSRhypothalamus — 7.2 nTPM, from INSRthalamus — no resolved target expressed herebasal ganglia — 6.2 nTPM, from INSRmedulla oblongata — no resolved target expressed here

basal ganglia: drawn as the caudate nucleus, putamen and globus pallidus.

Measured but not drawn — this anatomogram has no outline for them: pituitary gland 15.8, spinal cord 9.0, midbrain 7.2, retina 6.1.

Body

heart — 24.2 nTPM, from INSRsmooth muscle — 10.7 nTPM, from INSRlung — 6.7 nTPM, from INSRliver — 30.9 nTPM, from INSRkidney — 20.3 nTPM, from INSRstomach — 11.7 nTPM, from INSRduodenum — 9.4 nTPM, from INSRsmall intestine — 11.6 nTPM, from INSRcolon — 14.0 nTPM, from INSRadrenal gland — 21.9 nTPM, from INSRthyroid gland — 13.6 nTPM, from INSRpancreas — 60.3 nTPM, from INSRurinary bladder — 12.1 nTPM, from INSRskeletal muscle — 21.5 nTPM, from INSRspleen — 45.8 nTPM, from INSRsalivary gland — 16.1 nTPM, from INSR
060 nTPM

Square-root ramp · shared scale across both plates

Shading is transcript level — not affinity, and not affinity combined with expression. Outlined but unshaded organs hold none of INSR transcript above the atlas’s detection threshold. Anatomy from EMBL-EBI Anatomogram (Apache License 2.0); regions identified by Uberon (uberon.org), CC BY 3.0.

Brain · 10

  • pituitary gland15.8 nTPM
  • cerebellum11.6 nTPM
  • spinal cord9.0 nTPM
  • hippocampal formation7.3 nTPM
  • hypothalamus7.2 nTPM
  • midbrain7.2 nTPM
  • cerebral cortex6.7 nTPM
  • basal ganglia6.2 nTPM
  • retina6.1 nTPM
  • amygdala6.0 nTPM

Peripheral and autonomic · 16

  • pancreas60.3 nTPM
  • spleen45.8 nTPM
  • liver30.9 nTPM
  • heart muscle24.2 nTPM
  • adrenal gland21.9 nTPM
  • skeletal muscle21.5 nTPM
  • kidney20.3 nTPM
  • salivary gland16.1 nTPM
  • colon14.0 nTPM
  • thyroid gland13.6 nTPM
  • urinary bladder12.1 nTPM
  • stomach 111.7 nTPM
  • small intestine11.6 nTPM
  • smooth muscle10.7 nTPM
  • duodenum9.4 nTPM
  • lung6.7 nTPM

Transcript is not protein. These are RNA levels for INSR, shaded on √nTPM so that a three-order range stays legible — on a linear ramp every region but the strongest would read as blank, which looks like absence rather than less. A region carrying no shading is one the atlas reports no consensus value for, not one where the gene is silent. And a gene being transcribed somewhere is not evidence that any compound reaches it. Human Protein Atlas, RNA expression, nTPM (normalized transcripts per million), consensus tissue dataset.

IV · Evidence

Every measurement at this target

Each row links to the ChEMBL assay it came from.

Equilibrium binding constants 7

Ki and Kd — a concentration at equilibrium. Directly comparable across rows at the same target.

TargetClassTypeValue (nM)pXOrganismAssay
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsKi— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160

Functional readouts 7

IC₅₀, EC₅₀, AC₅₀ and potency. Assay-dependent, and not interchangeable with a binding constant.

TargetClassTypeValue (nM)pXOrganismAssay
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
Insulin receptorOther named receptorsIC50— no normalized value— value does not convert to pXRattus norvegicusCHEMBL1909160
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