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Updated November 2019

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Nomenclature

Short Name:
IRR
Full Name:
Insulin receptor-related protein
Alias:
  • EC 2.7.1.112
  • EC 2.7.10.1
  • INSRR
  • Insulin receptor-related protein precursor
  • IR-related receptor

Classification

Type:
Protein-tyrosine kinase
Group:
TK
Family:
InsR
SubFamily:
NA
 
 

Specific Links

Entrez-Gene Entry: 3645
Entrez-Protein Entry: NP_055030
GeneCards Entry: IRR
KinBASE Entry: IRR
OMIM Entry: 147671
Pfam Entry: P14616
PhosphoNET Entry: P14616
Phosphosite Plus Entry: 1937
ScanSite Entry: P14616
Source Entry: INSRR
UCSD-Nature Entry: A001280
UniProt Entry: P14616
Kinexus Products: IRR
Insulin receptor-related protein pan-specific antibody AB-NK273-1
IRS1 (979-989) KinSub - Insulin receptor substrate 1 (K979-G989, mouse) peptide; Insulin receptor substrate - Powder PE-01ADC95
Insulin receptor-related protein (R1269-C1288, human) peptide - Powder PE-01BDJ85

General Links

ClustalW2
GPS-Cuckoo
Human Protein Atlas
Kinase.com
Kinase Research
Kinasource
Kinomer
Netphorest
NetworKIN
Phosida
PhosphoElm
Protein Blast
ScanSite
String

Structure

Mol. Mass (Da):
143,720
# Amino Acids:
1297
# mRNA Isoforms:
1
mRNA Isoforms:
143,720 Da (1297 AA; P14616)
4D Structure:
Probable tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains contribute to the formation of the ligand-binding domain, while the beta chains carry the kinase domain.
1D Structure:
Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence
 
Subfamily Alignment
subfamily domain
 
Domain Distribution:
Start End Domain
1 23 signal_peptide
47 159 Recep_L_domain
173 329 Furin-like
346 461 Recep_L_domain
484 594 FN3
605 686 FN3
815 909 FN3
922 944 TMD
979 1246 TyrKc
979 1254 Pkinase
 

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
○ Insulin receptor-related protein pan-specific antibody AB-NK273-1
○ IRS1 (979-989) KinSub - Insulin receptor substrate 1 (K979-G989, mouse) peptide; Insulin receptor substrate - Powder PE-01ADC95
○ Insulin receptor-related protein (R1269-C1288, human) peptide - Powder PE-01BDJ85
 

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET
Tyrosine phosphorylated:

Y597, Y783, Y994.
N-GlcNAcylated:
N47, N311, N411, N492, N528, N616, N634, N756, N885, N898.
Serine phosphorylated:

S542, S553, S775, S1124, S1271.
Threonine phosphorylated:

T781, T1128, T1284.
 

Distribution

Based on gene microarray analysis from the NCBI
Human Tissue Distribution
% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:
% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:
  • adipose
    28

    289

    16

    377

  • adrenal
    1

    11

    8

    10

  • bladder
    1

    14

    1

    0

  • brain
    25

    259

    38

    485

  • breast
    21

    213

    14

    212

  • cervix
    0.5

    5

    37

    3

  • colon
    0.4

    4

    15

    4

  • heart
    61

    634

    13

    675

  • intestine
    18

    188

    10

    191

  • kidney
    1

    15

    31

    11

  • liver
    3

    26

    10

    36

  • lung
    66

    682

    61

    525

  • lymphnode
    1

    10

    12

    4

  • ovary
    1

    10

    6

    8

  • pancreas
    1

    11

    7

    8

  • pituitary
    0.7

    7

    7

    4

  • prostate
    0.9

    9

    13

    10

  • salivarygland
    1

    11

    6

    10

  • skeletalmuscle"
    3

    28

    37

    19

  • skin
    20

    211

    56

    270

  • spinalcord
    1

    15

    6

    13

  • spleen
    0.9

    9

    8

    6

  • stomach
    1

    15

    2

    3

  • testis
    2

    18

    6

    19

  • thymus
    0.9

    9

    6

    10

  • thyroid
    48

    497

    22

    523

  • tonsil
    1

    12

    15

    17

  • trachea
    1

    15

    6

    14

  • uterus
    1

    10

    6

    8

  • reticulocytes"
    21

    217

    14

    99

  • t-lymphocytes
    41

    422

    18

    306

  • b-lymphocytes
    100

    1037

    21

    1562

  • neutrophils
    46

    475

    87

    1018

  • macrophages
    71

    738

    26

    643

  • sperm
    7

    68

    22

    58

 

Evolution

Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
  • tableheader
    100

    100

    100
  • tableheader
    22.2

    37.2

    99.5
  • tableheader
    54.3

    69.1

    -
  • tableheader
    -

    -

    93
  • tableheader
    -

    -

    -
  • tableheader
    92.4

    95.5

    93
  • tableheader
    -

    -

    -
  • tableheader
    88.8

    92.8

    89
  • tableheader
    54.2

    69

    89
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    21.3

    33.5

    75
  • tableheader
    52.6

    67.7

    68
  • tableheader
    50.9

    65.1

    -
  • tableheader
    -

    -

    -
  • tableheader
    26

    36.7

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
 

Binding Proteins

Examples of known interacting proteins
hiddentext
No. Name – UniProt ID
1 KRT27 - Q7Z3Y8
2 INSR - P06213
3 SNAP29 - O95721
4 IRS1 - P35568
 

Regulation

Activation:
NA
Inhibition:
NA
Synthesis:
NA
Degradation:
NA
 

Protein Kinase Specificity

Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites

Kinections GIF
Matrix Type:
Predicted from the application of the Kinexus Kinase Substrate Predictor Version 2.0 algorithm, which was trained with over 10,000 kinase-protein substrate pairs and 8,000 kinase-peptide substrate pairs.
Domain #:
1
 

Inhibitors

For further details on these inhibitors click on the Compound Name and enter it into DrugKiNET or click on the ID's
Based on in vitro and/or in vivo phosphorylation data
Compound Name KD, Ki or IC50 (nM) PubChem ID ChEMBL ID PubMed ID
Hesperadin Kd < 10 nM 10142586 514409 19035792
Linsitinib IC50 = 75 nM 11640390 1091644 21425998
AT9283 IC50 > 100 nM 24905142 19143567
Tozasertib Kd = 276 nM 5494449 572878 19035792
MK5108 IC50 > 1 µM 24748204 20053775
Ponatinib IC50 > 1 µM 24826799 20513156
Silmitasertib IC50 > 1 µM 24748573 21174434
SNS314 IC50 > 1 µM 16047143 514582 18678489
SureCN2505235 IC50 = 1 µM 23649240 22934575
SureCN2579964 IC50 = 1 µM 290221 233000 22934575
WZ3146 Kd > 1 µM 44607360 20033049
WZ4002 Kd > 1 µM 44607530 20033049
GDC-0068 IC50 < 2.5 µM 24995523 22934575
JNJ-28871063 IC50 > 4 µM 17747413 17975007
 

Disease Linkage

General Disease Association:

Cancer, endocrine, neurological, and musculoskeletal disorders
Specific Diseases (Non-cancerous):

Hyperinsulinemic hypoglycemia, familial, 5; Diabetes mellitus, insulin-resistant, with acanthosis nigricans; Donohue syndrome; Rabson-Mendenhall syndrome; Insulin resistance; Alzheimer's disease (AD); Myotonic dystrophy; Acanthosis nigricans; Ovarian disease; Hyperinsulinemic hypoglycemia; Diabetes mellitus, Type 2; Diabetes mellitus, noninsulin-dependent, late onset; Hypertension, Insulin resistance-related; Hemihypertrophy; Congenital fiber-type disproportion (CFTD); Myotonic dystrophy Type 2 (DM2); Acanthocytosis; Berardinelli-Seip congenital lipodystrophy (BSCL); Fetal macrosomia; Fasting hypoglycemia; Insulin autoimmune syndrome
Comments:
Hyperinsulinemic Hypoglycemia, Familial, 5 is a rare disorder where insulin is overproduced because of insulin receptor deficiency. Diabetes Mellitus, Insulin-Resistant, with Acanthosis Nigricans is a rare disease with insulin-resistance that can affect bone and skin tissues. Donohue Syndrome is a rare syndrome where sufferers have greatly impaired insulin receptors and are characterized by elfin features, and smaller size (in stature). Rabson-Mendenhall Syndrome is a rare disorder with severe resistance to insulin resulting in impaired intrauterine and post-natal growth, increased volume of muscle and fat tissues, and physical abnormalities of the face, head, teeth, and nails. Alzheimer's disease (AD) is a rare neuro-degenerative disease that affects the thought, memory, and language portion of the brain. Myotonic Dystrophy is a rare disease that results in progressive muscle loss, typically in the face, neck, lower legs, and hands. Myotonic Dystrophy can affect skeletal muscle, brain, and heart. The rare skin disease, Acanthosis Nigricans, is characterized by making the folds and crevices of skin darker, thick, and velvety. Ovarian Disease is similar to the disorders insulin resistance and mccune albright syndrome. Sufferers of Type 2 Diabetes Mellitus have insulin resistance and excess blood glucose levels. Diabetes Mellitus, Noninsulin-Dependent, Late Onset is characterized by hyperglycemia (high blood glucose levels) induced by a reduced level of insulin production (but not fully abrogated, as would be the case in Type I diabetes). Diabetes Mellitus, Noninsulin-Dependent, Late Onset is similar to the familial hyperinsulinism and hyperinsulinemic hypoglycemia conditions. Hypertension, Insulin Resistance-Related is similar to the maturity-onset diabetes of the young and hyperandrogenism disorders. Diabetes Mellitus, Noninsulin-Dependent, Association with is related to the disorders maturity-onset diabetes of the young, and hyperinsulinism. Hemihypertrophy is a rare disease characterized by one side or part of the sufferer's body being larger than the other. Hemihypertrophy can be characterized by nephroblastoma (cancer of kidneys), asymmetrical rib cage, cognitive impairment, and other learning disabilities. The rare condition Congenital Fiber-Type Disproportion (CFTD) affects skeletal muscles required for movement, especially the hips, thighs, upper arms, shoulders, but also the eyelids, eye muscles (opthalmoplegia), breathing, and muscles for swallowing. Myotonic Dystrophy Type 2 (DM2) often correlates with sustained muscle tensing, and muscle weakness, pain, and stiffness. DM2 can also cause cataract opacification, and myotonia while affecting the eye, heart, and pancreatic tissues. The rare disease Acanthocytosis causes malformed red blood cells resulting in symptoms including chronic foul-smelling diarrhea, reduced growth, increased weight gain, and appetite loss. Berardinelli-Seip Congenital Lipodystrophy (BSCL) is noted for the lack of adipose (fatty) tissue in individuals with this disorder. Fetal Macrosomia is a rare disease similar to the gestational diabetes and diabetes mellitus disorders. Fetal Macrosomia can affect the testes and placenta. Fasting Hypoglycemia is related to the hypoglycemia and insulinoma disorders where there are high levels of insulin resulting in low blood glucose levels. Insulin Autoimmune Syndrome is characterized by the production of autoimmune antibodies targeting insulin.
 
Specific Cancer Types:
Brain cancer; Hemihypertrophy
Comments:
Hemihypertrophy can be characterized by nephroblastoma (cancer of kidneys), asymmetrical rib cage, cognitive impairment, and other learning disabilities.
 
Gene Expression in Cancers:

The COSMIC website notes an up-regulated expression score for IRR in diverse human cancers of 322, which is 0.7-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 0 for this protein kinase in human cancers was 100% lower than the average score of 60 for the human protein kinases.
Mutagenesis Experiments:

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis. Mutations that can inhibit IRR autophosphorylation are Y1145F with Y1146F.
Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.08 % in 25455 diverse cancer specimens. This rate is only 13 % higher than the average rate of 0.075 % calculated for human protein kinases in general.
Mutation Rate in Specific Cancers:

Highest percent mutation rates per 100 amino acids length in human cancers: 0.54 % in 895 skin cancers tested; 0.33 % in 603 endometrium cancers tested; 0.25 % in 1270 large intestine cancers tested; 0.22 % in 589 stomach cancers tested; 0.15 % in 1956 lung cancers tested; 0.12 % in 65 Meninges cancers tested; 0.08 % in 548 urinary tract cancers tested; 0.08 % in 273 cervix cancers tested; 0.08 % in 1512 liver cancers tested; 0.07 % in 891 ovary cancers tested; 0.06 % in 1467 pancreas cancers tested; 0.06 % in 1364 kidney cancers tested; 0.06 % in 127 biliary tract cancers tested; 0.05 % in 710 oesophagus cancers tested; 0.05 % in 1490 breast cancers tested.
Frequency of Mutated Sites:

Most frequent mutations with the number of reports indicated in brackets: R1072* (5).
Comments:
Only 2 deletions, 1 insertion, and no complex mutations are noted on the COSMIC website.
 
COSMIC Entry:
INSRR
OMIM Entry:
147671
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