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Updated November 2019

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Nomenclature

Short Name:
INSR
Full Name:
Insulin receptor
Alias:
  • EC 2.7.10.1
  • IR
  • Kinase InsR
  • CD220
  • CD220 antigen
  • HHF5
  • Insulin receptor

Classification

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

Specific Links

BioCarta Entry: insulin pathway
Entrez-Gene Entry: 3643
Entrez-Protein Entry: NP_000199
GeneCards Entry: CD220
KinBASE Entry: INSR
OMIM Entry: 147670
Pfam Entry: P06213
PhosphoNET Entry: P06213
Phosphosite Plus Entry: 608
Protein Data Bank Entry: 1GAG
ScanSite Entry: P06213
UCSD-Nature Entry: A001190
UniProt Entry: P06213
Kinexus Products: INSR
Insulin receptor pan-specific antibody AB-NK079-2
Insulin receptor Y1189 phosphosite-specific antibody AB-PK663
IRS1 (979-989) KinSub - Insulin receptor substrate 1 (K979-G989, mouse) peptide; Insulin receptor substrate - Powder PE-01ADC95
Insulin receptor (S1348-G1366, human) peptide - Powder PE-01BDI85
InsRSelectide - Insulin receptor protein kinase substrate peptide - Powder PE-01BHO95
InsRSubtide - InsR protein kinase substrate peptide - Powder PE-01BHP95
Insulin receptor ((1183-1195 ) pY1189, human) phosphopeptide - Powder PE-04AAJ90
Insulin receptor (E1186-K1192, human) pY1189 phosphopeptide - Powder PE-04AKM99

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):
156,319
# Amino Acids:
1382
# mRNA Isoforms:
2
mRNA Isoforms:
156,333 Da (1382 AA; P06213); 155,146 Da (1370 AA; P06213-2)
4D Structure:
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. Interacts with SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Interacts with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Forms a hybrid receptor with IGF1R, the hybrid is a tetramer consisting of 1 alpha chain and 1 beta chain of INSR and 1 alpha chain and 1 beta chain of IGF1R. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with Tyr-27 phosphorylation of CAV2. Interacts with ARRB2 By similarity. Interacts with GRB10; this interaction blocks the association between IRS1/IRS2 and INSR, significantly reduces insulin-stimulated tyrosine phosphorylation of IRS1 and IRS2 and thus decreases insulin signaling.
3D Structure:
Download QuickTime Animation
1D Structure:
Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence
 
3D Image (rendered using PV Viewer):

PDB ID
1IRK

Subfamily Alignment
subfamily domain
 
Domain Distribution:
Start End Domain
1 27 signal_peptide
52 164 Recep_L_domain
179 340 Furin-like
359 474 Recep_L_domain
622 695 FN3
850 946 FN3
957 979 TMD
1023 1290 TyrKc
1023 1298 Pkinase
 

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
○ Insulin receptor pan-specific antibody AB-NK079-2
○ Insulin receptor Y1189 phosphosite-specific antibody AB-PK663
○ IRS1 (979-989) KinSub - Insulin receptor substrate 1 (K979-G989, mouse) peptide; Insulin receptor substrate - Powder PE-01ADC95
○ Insulin receptor (S1348-G1366, human) peptide - Powder PE-01BDI85
○ InsRSelectide - Insulin receptor protein kinase substrate peptide - Powder PE-01BHO95
○ InsRSubtide - InsR protein kinase substrate peptide - Powder PE-01BHP95
○ Insulin receptor ((1183-1195 ) pY1189, human) phosphopeptide - Powder PE-04AAJ90
○ Insulin receptor (E1186-K1192, human) pY1189 phosphopeptide - Powder PE-04AKM99
 

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET
Acetylated:
K1112 (N6).
Methylated:
K1352.
N-GlcNAcylated:
N43, N52, N105, N138, N242, N282, N322, N364, N424, N445, N541, N633, N651,N698, N769, N782, N920, N933.
Serine phosphorylated:

S98, S366, S400, S407, S464, S717, S929, S1033, S1062, S1064, S1216+, S1217+, S1221+, S1314, S1332+, S1333+, S1348, S1354.
Threonine phosphorylated:

T361, T715, T731, T940, T1187, T1362, T1375+.
Tyrosine phosphorylated:

Y94, Y401, Y818, Y992-, Y999+, Y1011-, Y1038, Y1149, Y1185+, Y1189+, Y1190+, Y1355+, Y1356, Y1361+.
Ubiquitinated:
K1047, K1057, K1352.
 

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
    100

    1289

    53

    1012

  • adrenal
    16

    205

    21

    315

  • bladder
    10

    131

    22

    127

  • brain
    25

    320

    206

    875

  • breast
    77

    993

    65

    690

  • cervix
    7

    86

    110

    131

  • colon
    28

    357

    75

    572

  • heart
    26

    336

    65

    523

  • intestine
    46

    587

    17

    516

  • kidney
    43

    559

    209

    780

  • liver
    9

    122

    50

    122

  • lung
    49

    636

    236

    702

  • lymphnode
    4

    47

    44

    51

  • ovary
    14

    185

    15

    313

  • pancreas
    25

    318

    45

    410

  • pituitary
    16

    211

    36

    168

  • prostate
    11

    148

    373

    855

  • salivarygland
    11

    146

    33

    189

  • skeletalmuscle"
    16

    204

    181

    230

  • skin
    63

    816

    221

    694

  • spinalcord
    6

    77

    43

    80

  • spleen
    15

    193

    46

    234

  • stomach
    8

    98

    40

    96

  • testis
    4

    54

    33

    53

  • thymus
    4

    56

    43

    86

  • thyroid
    79

    1013

    137

    1068

  • tonsil
    4

    55

    47

    61

  • trachea
    10

    125

    33

    117

  • uterus
    11

    138

    33

    145

  • reticulocytes"
    10

    130

    84

    92

  • t-lymphocytes
    38

    492

    24

    496

  • b-lymphocytes
    27

    354

    56

    427

  • neutrophils
    11

    140

    115

    379

  • macrophages
    65

    838

    166

    739

  • sperm
    15

    199

    87

    276

 

Evolution

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

    100

    100
  • tableheader
    22.1

    36.3

    100
  • tableheader
    -

    -

    99
  • tableheader
    -

    -

    97
  • tableheader
    -

    -

    98
  • tableheader
    93.6

    95.6

    95.5
  • tableheader
    -

    -

    -
  • tableheader
    94.5

    96.7

    96
  • tableheader
    94.6

    97

    96
  • tableheader
    -

    -

    -
  • tableheader
    -

    -

    -
  • tableheader
    21.3

    35.3

    84
  • tableheader
    70.5

    81.8

    73.5
  • tableheader
    68.5

    81

    71
  • tableheader
    -

    -

    -
  • tableheader
    27.6

    38.7

    37
  • tableheader
    -

    -

    -
  • tableheader
    28.3

    42.4

    31
  • 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 PTPN1 - P18031
2 IRS1 - P35568
3 GRB10 - Q13322
4 GRB14 - Q14449
5 SHC1 - P29353
6 PIK3R1 - P27986
7 PTPN11 - Q06124
8 IRS2 - Q9Y4H2
9 SOCS1 - O15524
10 CALM1 - P62158
11 SOCS3 - O14543
12 INS - P01308
13 JAK2 - O60674
14 PRKCD - Q05655
15 SH2B1 - Q9NRF2
 

Regulation

Activation:
Phosphorylation of Ser-1001, Ser-1332, Ser-1333, Tyr-1355, Tyr-1361, Thr-1375 increases phosphotransferase activity. Phosphorylation of Tyr-999 increases phosphotransferase activity and induces interaction with SOCS3. Phosphorylation of Tyr-1185 increases phosphotransferase activity and induces interaction with IRS2 and PTP1B. Phosphorylation of Tyr-1189 and Tyr-1190 increases phosphotransferase activity and induces interaction with IRS2 and PTP1B.
Inhibition:
Phosphorylation of Tyr-992, Tyr-1011 inhibits phosphotransferase activity.
Synthesis:
NA
Degradation:
NA
 

Kinections Map

Click here to download a PPT of the image below
 
Kinections GIF
 

Known Upstream Kinases

For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET predictions.
Based on in vitro and/or in vivo phosphorylation data

Kinase Short Name UniProt ID (Human) Phosphosite Location Phosphosite Sequence Effect of Phosphorylation
INSR P06213 Y992 DGPLGPLYASSNPEY -
INSR P06213 Y999 YASSNPEYLSASDVF +
INSR P06213 Y1011 DVFPCSVYVPDEWEV -
TBK1 Q9UHD2 S1033 LRELGQGSFGMVYEG
PKCa P17252 S1062 AVKTVNESASLRERI
PKCa P17252 S1064 KTVNESASLRERIEF
INSR P06213 Y1185 FGMTRDIYETDYYRK +
INSR P06213 Y1189 RDIYETDYYRKGGKG +
INSR P06213 Y1190 DIYETDYYRKGGKGL +
INSR P06213 S1314 EENKAPESEELEMEF
INSR P06213 S1348 GGRDGGSSLGFKRSY
INSR P06213 Y1355 SLGFKRSYEEHIPYT +
INSR P06213 Y1356 SLSIKRTYDEHIPYT
INSR P06213 Y1361 SYEEHIPYTHMNGGK +
PKCa P17252 T1375 KKNGRILTLPRSNPS +
 

Known Downstream Substrates

For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET predictions.
Based on in vitro and/or in vivo phosphorylation data

Substrate Short Name UniProt ID (Human) Phosphosite Location Phosphosite Sequence Effect of Phosphorylation
ADRB2 P07550 Y132 CVIAVDRYFAITSPF
ADRB2 P07550 Y141 AITSPFKYQSLLTKN
ADRB2 P07550 Y350 RRSSLKAYGNGYSSN
ADRB2 P07550 Y354 LKAYGNGYSSNGNTG
ANXA1 P04083 Y20 IENEEQEYVQTVKSS
APS O14492 Y629 ARAVENQYSFY____
ARHGAP5 Q13017 Y306 NHPDYEEYINLEGTR
BLVRA (BVA) P53004 Y198 EERKEDQYMKMTVCL +
BLVRA (BVA) P53004 Y228 PGLKRNRYLSFHFKS
BLVRA (BVA) P53004 Y291 LAEEIQKYCCSRK__
Calmodulin P62158 Y139 DGDGQVNYEEFVQMM
Calmodulin P62158 Y99 FDKDGNGYISAAELR
Caveolin 1 (CAV1) Q03135 Y14 VDSEGHLYTVPIREQ
Cbl P22681 Y371 TQEQYELYCEMGSTF
Cbl P22681 Y700 EGEEDTEYMTPSSRP
Cbl P22681 Y774 SENEDDGYDVPKPPV
CEACAM1 P13688 S508 QQPTQPTSASPSLTA
CEACAM1 P13688 Y493 NKMNEVTYSTLNFEA
CEACAM1 P13688 Y520 LTATEIIYSEVKKQ_
Dok1 p62 Q99704 Y362 DPKEDPIYDEPEGLA +
Dok1 p62 Q99704 Y398 ARVKEEGYELPYNPA +
FABP4 P15090 Y19 SSENFDDYMKEVGVG
GAB1 Q13480 Y242 FFQQQMIYDSPPSRA
GAB1 Q13480 Y285 TEADGELYVFNTPSG
GAB1 Q13480 Y373 ASDTDSSYCIPTAGM
GAB1 Q13480 Y447 SEELDENYVPMNPNS
GAB1 Q13480 Y472 EPIQEANYVPMTPGT
GAB1 Q13480 Y589 SHDSEENYVPMNPNL
GAB1 Q13480 Y627 KGDKQVEYLDLDLDS
GAB1 Q13480 Y659 VADERVDYVVVDQQK
IkBa P25963 Y42 DSMKDEEYEQMVKEL -
InsR P06213 S1314 EENKAPESEELEMEF
InsR P06213 S1348 GGRDGGSSLGFKRSY
InsR P06213 Y1011 DVFPCSVYVPDEWEV -
InsR P06213 Y1185 FGMTRDIYETDYYRK +
InsR P06213 Y1189 RDIYETDYYRKGGKG +
InsR P06213 Y1190 DIYETDYYRKGGKGL +
InsR P06213 Y1355 SLGFKRSYEEHIPYT +
InsR P06213 Y1356 SLSIKRTYDEHIPYT
InsR P06213 Y1361 SYEEHIPYTHMNGGK +
InsR P06213 Y992 DGPLGPLYASSNPEY -
InsR P06213 Y999 YASSNPEYLSASDVF +
IRS1 P35568 S1222 ESSSTRRSSEDLSAY
IRS1 P35568 Y1179 GLENGLNYIDLDLVK
IRS1 P35568 Y1222 SSEDLSTYASINFQK
IRS1 P35568 Y1229 SSEDLSAYASISFQK
IRS1 P35568 Y465 GEEELSNYICMGGKG
IRS1 P35568 Y612 TLHTDDGYMPMSPGV
IRS1 P35568 Y632 GRKGSGDYMPMSPKS
IRS1 P35568 Y896 EPKSPGEYVNIEFGS ?
IRS1 P35568 Y941 EETGTEEYMKMDLGP
IRS1 P35568 Y989 VPSSRGDYMTMQMSC
IRS2 Q9Y4H2 Y628 PKVAYHPYPEDYGDI -
IRS2 Q9Y4H2 Y632 YHPYPEDYGDIEIGS
PIK3R1 P27986 Y368 STKMHGDYTLTLRKG
PIK3R1 P27986 Y580 LRKTRDQYLMWLTQK
PIK3R1 P27986 Y607 NENTEDQYSLVEDDE
PIK3R3 Q92569 Y341 NEDADENYFINEEDE
PPP2CA P67775 Y307 VTRRTPDYFL_____ +
PTPN6 (SHP1) P29350 Y536 QKGQESEYGNITYPP +
SOCS3 O14543 Y204 VNGHLDSYEKVTQLP
STAT5B P51692 Y699 TAKAVDGYVKPQIKQ +
 

Protein Kinase Specificity

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

Kinections GIF
Matrix Type:
Experimentally derived from alignment of 79 known protein substrate phosphosites and 31 peptides phosphorylated by recombinant INSR in vitro tested in-house by Kinexus.
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
BMS-754807 IC50 = 1.7 nM 24785538 19996272
GSK1838705A Kd = 1.7 nM 25182616 464552 22037378
NVP-TAE684 Kd = 2.4 nM 16038120 509032 22037378
Aminopurvalanol A IC50 = 4.4 nM 6604931 12678910
Staurosporine IC50 = 8.5 nM 5279 19397322
Hesperadin Kd < 10 nM 10142586 514409 19035792
GSK1904529A IC50 = 19 nM 25124816 466397 19101143
Nintedanib Kd = 24 nM 9809715 502835 22037378
Princeton's TrkA inhibitor compound 20h IC50 < 40 nM
AC480 IC50 51 nM 46930994 566113
BMS-536924 IC50 = 73 nM 10390396 401930 16134929
Linsitinib IC50 = 75 nM 11640390 1091644 21425998
Kinome_714 IC50 = 80 nM 46886323 20346655
R406 IC50 < 80 nM 11984591
AT9283 IC50 > 100 nM 24905142 19143567
BML-275 IC50 = 100 nM 11524144 478629
Purvalanol B IC50 < 100 nM 448991 23254
Semaxinib IC50 = 100 nM 5329098 276711
Staurosporine aglycone IC50 < 100 nM 3035817 281948
STO609 IC50 = 100 nM 51371511
Syk Inhibitor IC50 = 100 nM 6419747 104279
Syk Inhibitor IV IC50 = 100 nM 10200390
Crizotinib IC50 = 102 nM 11626560 601719 21812414
AG-E-60384 IC50 > 150 nM 6419741 413188 22037377
SB218078 IC50 > 150 nM 447446 289422 22037377
Sunitinib Kd = 180 nM 5329102 535 15711537
Foretinib Kd = 210 nM 42642645 1230609 22037378
GSK-3 Inhibitor XIII IC50 > 250 nM 6419766 359482 22037377
K-252a; Nocardiopsis sp. IC50 > 250 nM 3813 281948 22037377
PDK1/Akt/Flt Dual Pathway Inhibitor IC50 > 250 nM 5113385 599894 22037377
SU11652 IC50 > 250 nM 24906267 13485 22037377
K00596a IC50 < 400 nM 9549298 200027
KW2449 Kd = 400 nM 11427553 1908397 22037378
TTT-3002 IC50 < 400 nM
IDR E804 IC50 = 500 nM 6419764 1802727 22037377
Tozasertib Kd = 506 nM 5494449 572878 19035792
Amgen TBK 1 inhibitor (Compound II) IC50 < 600 nM
GSK-3 Inhibitor IX IC50 < 800 nM 5287844 409450
SU6656 IC50 < 800 nM 5353978 605003
TG101348 Kd = 850 nM 16722836 1287853 22037378
BX517 IC50 > 900 nM 11161844 228654
CZC-25146 IC50 = 1 µM
GW441756 hydrochloride IC50 = 1 µM 16219400
IKK-2 Inhibitor VIII IC50 = 1 µM 66576999 368427
Imatinib IC50 = 1 µM 123596 941
Indirubin-3′-monoxime IC50 > 1 µM 5326739 22037377
MK5108 IC50 > 1 µM 24748204 20053775
Ponatinib IC50 > 1 µM 24826799 20513156
Purvalanol A IC50 = 1 µM 456214 23327
Regorafenib IC50 > 1 µM 11167602 21170960
Silmitasertib IC50 > 1 µM 24748573 21174434
SNS314 IC50 > 1 µM 16047143 514582 18678489
SureCN10063060 Ki > 1 µM 52936621 21391610
SureCN2579964 IC50 = 1 µM 24948986 22934575
SureCN4139760 IC50 > 1 µM 25065806 18691885
Syk Inhibitor II IC50 = 1 µM 16760670
Tivozanib IC50 > 1 µM 9911830 16982756
Vemurafenib IC50 = 1 µM 42611257 1229517
WZ3146 Kd > 1 µM 44607360 20033049
WZ4002 Kd > 1 µM 44607530 20033049
Lestaurtinib Kd = 1.1 µM 126565 22037378
SU14813 Kd = 1.2 µM 10138259 1721885 18183025
2hiw EC50 > 2 µM 10062694 18077425
BMS-777607 IC50 > 2 µM 24794418 19260711
Momelotinib IC50 > 2 µM 25062766 19295546
PF-228 IC50 > 2 µM 11612883 17395594
AST-487 Kd = 2.2 µM 11409972 574738 22037378
AEW-541 IC50 = 2.3 µM 11476171 19610618
PHA-665752 Kd = 2.3 µM 10461815 450786 22037378
CHEMBL489083 IC50 = 2.6 µM 25178539 489083 19053831
ZINC00016978 IC50 = 2.6 µM 5329009 301018 19211246
CHEMBL1784637 IC50 > 3 µM 46864270 1784637 21561767
Neratinib Kd = 3 µM 9915743 180022 22037378
TG101209 IC50 > 3 µM 16722832 17541402
SureCN4875304 IC50 > 3.5 µM 46871765 20472445
BI-D1870 IC50 < 4 µM 25023738 573107
JNJ-28871063 IC50 > 4 µM 17747413 17975007
BX795 IC50 > 4.5 µM 10077147 577784
GSK461364A IC50 > 4.5 µM 15983966 1908394
JNKIN7 IC50 > 4.5 µM 57340685
JNKIN8 IC50 > 4.5 µM 57340686
 

Disease Linkage

General Disease Association:

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

Hyperinsulinemic hypoglycemia, familial, 5; Diabetes mellitus, Insulin-resistant, with acanthosis nigricans; Rabson-Mendenhall syndrome; Donohue syndrome; Diabetes mellitus, non-insulin-dependent, late onset; Hypertension, Insulin resistance-related; Alzheimer's disease; Myotonic dystrophy; Ovarian disease; Acanthosis nigricans; Hyperinsulinemic hypoglycemia; Obesity; Metabolic syndrome X; Hemi-hypertrophy; Congenital fiber-type disproportion; Myotonic dystrophy Type 2; Berardinelli-Seip congenital lipodystrophy; Acanthocytosis; Fetal macrosomia; Fasting hypoglycemia; Insulin autoimmune syndrome
Comments:
Hyperinsulinemic hypoglycemia is a condition characterized by low blood glucose resulting from the excessive release of insulin. This disease can be acquired during life or inherited and can range in severity from life-threatenting to a mild nuissance. Diabetes mellitus, insulin resistance with acanthosis nigricans is a disease characterized by combined symptoms of diabetes, insulin resistance, and acanthosis nigricans. Acanthosis nigricans is characterized by the hyperpigmentation of the skin, producing a brown to black, poorly defined, and velvety region of skin, which is usually found in the posterior and lateral folds of the neck, the armpits, navel, forehead, groin, and other body folds. Donohue syndrome, also known as Leprechanumism, is an extremely rare genetic disease characterized by stunted growth, protruding ears, flaring nostrils, and thick lips. Rabson-Mendenhall syndrome is a genetic disease characterized by a severe resistance to insulin. Symptoms of the disease include growth retardation, hypertrophy of muscle and fat tissues, and craniofacial, dental, and skin abnormalities. Several mutations in the INSR gene have been observed in patients with diabetes mellitus, insulin resistance, with acanthosis nigricans, including substitution mutations (G1035V, R762S, W1227S, A1161T, N489S, R1020Q, A1162E, R1201Q) and nonsense mutations (W160X). These mutations are associated with a loss-of-function , as many of them are found within the kinase catalytic domain of the protein. It was observed that a patient with Donohue syndrome displayed an 80-90% reduction in the amount of INSR in circulating monocytes, and those present had a significantly decreased responsiveness to temperature and pH. In addition, a marked reduction in INSR mRNA has also been demonstrated in the circulating monocytes of a patient with Donohue syndrome. Several mutations in the INSR gene have been observed in patients with Donohue syndrome, including substitution mutations (K487E, L260P, H236R, G58R, V55A, G393R, R113P, W439S, I146M, N458D) and nonsense mutations (Q699X, R924X, R399X, K148X). These mutations are also associated with a loss-of-function of the protein. In addition, two mutations in the INSR gene were observed in patients with Rabson-Medenhall syndrome. One was a A-G transition at the 3-prime splice site of intron 4 resulting in a decreased mRNA expression and a severely truncated protein. The other mutation was an 8-bp deletion in exon 12 of the gene. This mutation also decreased mRNA levels and produced a truncated protein. Thus, the phenotype of this disease is associated with a defective INSR protein. Several animal studies have revealed links between INSR and disease phenotypes. For example, genetically obese mice with insulin resistance were shown to have a mutation in the INSR gene, which decreased the tyrosine kinase catalytic activity of the protein. In addition, ablation of all INSR in mice resulted in the development of severe hyperglycemia and hyperketonia within hours of birth, resulting in death due to diabetic ketoacidosis within 48-72 hours of birth.
 
Specific Cancer Types:
Brain cancer
Comments:
INSR appears to be an oncoprotein (OP). over activation of the insulin receptor signalling pathway has been linked to the development of several cancer types. Significantly elevated INSR expression is observed in a high percentage of samples representing several subtypes of breast cancer (e. g. luminal; 48. 1%, triple negative; 41. 9%, and HER2; 64. 3%, of 438 specimens). In addition, elevated INSR expression in breast cancer is correlated with poor patient survival. Expression of phosphorylated INSR, as well as phosphoryalted IGF-1R and its downstream signalling target phospho-S6, were observed in 438 cases of invasive breast cancer samples. In eight breast cancer cell lines it was demonstrated that IGF-2 binds to and activates the INSR protein with 63% of the potency of insulin. By contrast, in non-malignant human breast cells, IGF-2 has about 1% the potency of insulin in binding to INSR. This activation of INSR by IGF-2 in cancer cells at much higher potency than in normal cells is hypothesized to lead to cancer cell growth and represent a novel autocrine/paracrine signalling mechanism by which cancer cells can promote survival and proliferation. Additionally, elevated INSR expression has been reported in breast cancer cell lines, higher than in any normal tissue investigated, including the liver. The INSR protein in the cancer cell retained the ability to bind to and be activated by insulin. INSR expression in the cancer specimens was restricted to the epithelial cells of the breast and was not obsrved in either the stromal or inflammatory cells present in the tissue samples. Additionally, there was no correlation between INSR expression level, age, body weight, menopausal status, or nodal involvement.
 
Gene Expression in Cancers:

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Barrett's esophagus epithelial metaplasia (%CFC= +285, p<0.017); Breast epithelial hyperplastic enlarged lobular units (HELU) (%CFC= -59, p<0.011); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +281, p<0.007); Oral squamous cell carcinomas (OSCC) (%CFC= +70, p<0.082); Pituitary adenomas (aldosterone-secreting) (%CFC= +61, p<0.017); and Prostate cancer - primary (%CFC= +72, p<0.0001). The COSMIC website notes an up-regulated expression score for INSR in diverse human cancers of 348, which is 0.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 23 for this protein kinase in human cancers was 0.4-fold of 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.
Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.07 % in 25404 diverse cancer specimens. This rate is only -5 % lower and is very similar to 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: 0.35 % in 864 skin cancers tested; 0.31 % in 1270 large intestine cancers tested; 0.24 % in 603 endometrium cancers tested; 0.21 % in 589 stomach cancers tested; 0.12 % in 710 oesophagus cancers tested; 0.12 % in 548 urinary tract cancers tested; 0.12 % in 238 bone cancers tested; 0.11 % in 1958 lung cancers tested; 0.08 % in 273 cervix cancers tested; 0.06 % in 891 ovary cancers tested; 0.06 % in 1512 liver cancers tested; 0.06 % in 1316 breast cancers tested; 0.06 % in 127 biliary tract cancers tested; 0.04 % in 1276 kidney cancers tested; 0.02 % in 942 upper aerodigestive tract cancers tested; 0.02 % in 939 prostate cancers tested; 0.02 % in 441 autonomic ganglia cancers tested; 0.02 % in 2082 central nervous system cancers tested; 0.02 % in 1467 pancreas cancers tested; 0.01 % in 558 thyroid cancers tested; 0 % in 2009 haematopoietic and lymphoid cancers tested.
Frequency of Mutated Sites:

Most frequent mutations with the number of reports indicated in brackets: A1340V (3).
Comments:
Only 2 deletions, and no insertions or complex mutations are noted on the COSMIC website.
 
COSMIC Entry:
INSR
OMIM Entry:
147670
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