Product: Phospho-IGF1R/Insulin Receptor (Tyr1161) Antibody
Catalog: AF3125
Source: Rabbit
Application: WB, IHC, IF/ICC, IP, ELISA(peptide)
Reactivity: Human, Mouse, Rat
Prediction: Bovine, Rabbit, Dog, Chicken, Xenopus
Mol.Wt.: 95kD,155kD; 155kD,156kD(Calculated).
Uniprot: P08069 | P06213
RRID: AB_2834560

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Product Info

Source:
Rabbit
Application:
WB 1:500-1:2000, IHC 1:50-1:200, IP, IF/ICC 1:100-1:500, ELISA(peptide) 1:20000-1:40000
*The optimal dilutions should be determined by the end user.
*Tips:

WB: For western blot detection of denatured protein samples. IHC: For immunohistochemical detection of paraffin sections (IHC-p) or frozen sections (IHC-f) of tissue samples. IF/ICC: For immunofluorescence detection of cell samples. ELISA(peptide): For ELISA detection of antigenic peptide.

Reactivity:
Human,Mouse,Rat
Prediction:
Bovine(100%), Rabbit(100%), Dog(100%), Chicken(100%), Xenopus(100%)
Clonality:
Polyclonal
Specificity:
Phospho-IGF1R/Insulin Receptor (Tyr1161) Antibody detects endogenous levels of IGF1R/Insulin Receptor only when phosphorylated at Tyrosine 1161.
RRID:
AB_2834560
Cite Format: Affinity Biosciences Cat# AF3125, RRID:AB_2834560.
Purification:
The antibody is from purified rabbit serum by affinity purification via sequential chromatography on phospho-peptide and non-phospho-peptide affinity columns.
Storage:
Rabbit IgG in phosphate buffered saline , pH 7.4, 150mM NaCl, 0.02% sodium azide and 50% glycerol. Store at -20 °C. Stable for 12 months from date of receipt.
Alias:

Fold/Unfold

CD221; CD221 antigen; IGF 1 receptor; IGF 1R; IGF I receptor; IGF-I receptor; Igf1r; IGF1R_HUMAN; IGFIR; IGFIRC; IGFR; Insulin like growth factor 1 receptor; Insulin like growth factor 1 receptor precursor; Insulin-like growth factor 1 receptor beta chain; Insulin-like growth factor I receptor; JTK13; MGC142170; MGC142172; MGC18216; Soluble IGF1R variant 1; Soluble IGF1R variant 2; CD220; HHF5; HIR B; INSR; Insulin receptor; Insulin receptor subunit beta; IR;

Immunogens

Immunogen:
Uniprot:
Gene(ID):
Expression:
P08069 IGF1R_HUMAN:

Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney.

P06213 INSR_HUMAN:

Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.

Description:
InsR a receptor tyrosine kinase that binds insulin and key mediator of the metabolic effects of insulin. Binding to insulin stimulates association of the receptor with downstream mediators including IRS1 and phosphatidylinositol 3'-kinase (PI3K).
Sequence:
MKSGSGGGSPTSLWGLLFLSAALSLWPTSGEICGPGIDIRNDYQQLKRLENCTVIEGYLHILLISKAEDYRSYRFPKLTVITEYLLLFRVAGLESLGDLFPNLTVIRGWKLFYNYALVIFEMTNLKDIGLYNLRNITRGAIRIEKNADLCYLSTVDWSLILDAVSNNYIVGNKPPKECGDLCPGTMEEKPMCEKTTINNEYNYRCWTTNRCQKMCPSTCGKRACTENNECCHPECLGSCSAPDNDTACVACRHYYYAGVCVPACPPNTYRFEGWRCVDRDFCANILSAESSDSEGFVIHDGECMQECPSGFIRNGSQSMYCIPCEGPCPKVCEEEKKTKTIDSVTSAQMLQGCTIFKGNLLINIRRGNNIASELENFMGLIEVVTGYVKIRHSHALVSLSFLKNLRLILGEEQLEGNYSFYVLDNQNLQQLWDWDHRNLTIKAGKMYFAFNPKLCVSEIYRMEEVTGTKGRQSKGDINTRNNGERASCESDVLHFTSTTTSKNRIIITWHRYRPPDYRDLISFTVYYKEAPFKNVTEYDGQDACGSNSWNMVDVDLPPNKDVEPGILLHGLKPWTQYAVYVKAVTLTMVENDHIRGAKSEILYIRTNASVPSIPLDVLSASNSSSQLIVKWNPPSLPNGNLSYYIVRWQRQPQDGYLYRHNYCSKDKIPIRKYADGTIDIEEVTENPKTEVCGGEKGPCCACPKTEAEKQAEKEEAEYRKVFENFLHNSIFVPRPERKRRDVMQVANTTMSSRSRNTTAADTYNITDPEELETEYPFFESRVDNKERTVISNLRPFTLYRIDIHSCNHEAEKLGCSASNFVFARTMPAEGADDIPGPVTWEPRPENSIFLKWPEPENPNGLILMYEIKYGSQVEDQRECVSRQEYRKYGGAKLNRLNPGNYTARIQATSLSGNGSWTDPVFFYVQAKTGYENFIHLIIALPVAVLLIVGGLVIMLYVFHRKRNNSRLGNGVLYASVNPEYFSAADVYVPDEWEVAREKITMSRELGQGSFGMVYEGVAKGVVKDEPETRVAIKTVNEAASMRERIEFLNEASVMKEFNCHHVVRLLGVVSQGQPTLVIMELMTRGDLKSYLRSLRPEMENNPVLAPPSLSKMIQMAGEIADGMAYLNANKFVHRDLAARNCMVAEDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMSPESLKDGVFTTYSDVWSFGVVLWEIATLAEQPYQGLSNEQVLRFVMEGGLLDKPDNCPDMLFELMRMCWQYNPKMRPSFLEIISSIKEEMEPGFREVSFYYSEENKLPEPEELDLEPENMESVPLDPSASSSSLPLPDRHSGHKAENGPGPGVLVLRASFDERQPYAHMNGGRKNERALPLPQSSTC

MATGGRRGAAAAPLLVAVAALLLGAAGHLYPGEVCPGMDIRNNLTRLHELENCSVIEGHLQILLMFKTRPEDFRDLSFPKLIMITDYLLLFRVYGLESLKDLFPNLTVIRGSRLFFNYALVIFEMVHLKELGLYNLMNITRGSVRIEKNNELCYLATIDWSRILDSVEDNYIVLNKDDNEECGDICPGTAKGKTNCPATVINGQFVERCWTHSHCQKVCPTICKSHGCTAEGLCCHSECLGNCSQPDDPTKCVACRNFYLDGRCVETCPPPYYHFQDWRCVNFSFCQDLHHKCKNSRRQGCHQYVIHNNKCIPECPSGYTMNSSNLLCTPCLGPCPKVCHLLEGEKTIDSVTSAQELRGCTVINGSLIINIRGGNNLAAELEANLGLIEEISGYLKIRRSYALVSLSFFRKLRLIRGETLEIGNYSFYALDNQNLRQLWDWSKHNLTITQGKLFFHYNPKLCLSEIHKMEEVSGTKGRQERNDIALKTNGDQASCENELLKFSYIRTSFDKILLRWEPYWPPDFRDLLGFMLFYKEAPYQNVTEFDGQDACGSNSWTVVDIDPPLRSNDPKSQNHPGWLMRGLKPWTQYAIFVKTLVTFSDERRTYGAKSDIIYVQTDATNPSVPLDPISVSNSSSQIILKWKPPSDPNGNITHYLVFWERQAEDSELFELDYCLKGLKLPSRTWSPPFESEDSQKHNQSEYEDSAGECCSCPKTDSQILKELEESSFRKTFEDYLHNVVFVPRKTSSGTGAEDPRPSRKRRSLGDVGNVTVAVPTVAAFPNTSSTSVPTSPEEHRPFEKVVNKESLVISGLRHFTGYRIELQACNQDTPEERCSVAAYVSARTMPEAKADDIVGPVTHEIFENNVVHLMWQEPKEPNGLIVLYEVSYRRYGDEELHLCVSRKHFALERGCRLRGLSPGNYSVRIRATSLAGNGSWTEPTYFYVTDYLDVPSNIAKIIIGPLIFVFLFSVVIGSIYLFLRKRQPDGPLGPLYASSNPEYLSASDVFPCSVYVPDEWEVSREKITLLRELGQGSFGMVYEGNARDIIKGEAETRVAVKTVNESASLRERIEFLNEASVMKGFTCHHVVRLLGVVSKGQPTLVVMELMAHGDLKSYLRSLRPEAENNPGRPPPTLQEMIQMAAEIADGMAYLNAKKFVHRDLAARNCMVAHDFTVKIGDFGMTRDIYETDYYRKGGKGLLPVRWMAPESLKDGVFTTSSDMWSFGVVLWEITSLAEQPYQGLSNEQVLKFVMDGGYLDQPDNCPERVTDLMRMCWQFNPKMRPTFLEIVNLLKDDLHPSFPEVSFFHSEENKAPESEELEMEFEDMENVPLDRSSHCQREEAGGRDGGSSLGFKRSYEEHIPYTHMNGGKKNGRILTLPRSNPS

Predictions

Predictions:

Score>80(red) has high confidence and is suggested to be used for WB detection. *The prediction model is mainly based on the alignment of immunogen sequences, the results are for reference only, not as the basis of quality assurance.

Species
Results
Score
Bovine
100
Dog
100
Xenopus
100
Chicken
100
Rabbit
100
Pig
0
Horse
0
Sheep
0
Zebrafish
0
Model Confidence:
High(score>80) Medium(80>score>50) Low(score<50) No confidence

PTMs - P08069/P06213 As Substrate

Site PTM Type Enzyme
N43 N-Glycosylation
N52 N-Glycosylation
T68 Phosphorylation
T85 Phosphorylation
Y87 Phosphorylation
Y94 Phosphorylation
S98 Phosphorylation
N138 N-Glycosylation
N242 N-Glycosylation
N282 N-Glycosylation
T361 Phosphorylation
N364 N-Glycosylation
S366 Phosphorylation
S400 Phosphorylation
Y401 Phosphorylation
S407 Phosphorylation
N424 N-Glycosylation
N445 N-Glycosylation
T447 Phosphorylation
Y457 Phosphorylation
S464 Phosphorylation
S473 Phosphorylation
N541 N-Glycosylation
S567 Phosphorylation
S682 Phosphorylation
T715 Phosphorylation
S717 Phosphorylation
K721 Ubiquitination
T731 Phosphorylation
N769 N-Glycosylation
Y818 Phosphorylation
N920 N-Glycosylation
S929 Phosphorylation
T940 Phosphorylation
Y992 Phosphorylation P06213 (INSR)
Y999 Phosphorylation P06213 (INSR)
Y1011 Phosphorylation P06213 (INSR)
K1022 Ubiquitination
S1033 Phosphorylation Q9UHD2 (TBK1)
Y1038 Phosphorylation
K1047 Ubiquitination
K1057 Ubiquitination
S1062 Phosphorylation P17252 (PRKCA)
S1064 Phosphorylation P17252 (PRKCA)
C1083 S-Nitrosylation
K1112 Acetylation
Y1149 Phosphorylation
C1165 S-Nitrosylation
Y1185 Phosphorylation P06213 (INSR)
T1187 Phosphorylation
Y1189 Phosphorylation P06213 (INSR)
Y1190 Phosphorylation P06213 (INSR)
K1192 Ubiquitination
K1195 Ubiquitination
S1216 Phosphorylation
S1217 Phosphorylation
S1221 Phosphorylation
C1261 S-Nitrosylation
C1272 S-Nitrosylation
S1314 Phosphorylation P06213 (INSR)
S1332 Phosphorylation P06213 (INSR)
S1333 Phosphorylation P06213 (INSR)
S1348 Phosphorylation P06213 (INSR)
K1352 Methylation
K1352 Ubiquitination
S1354 Phosphorylation
Y1355 Phosphorylation P06213 (INSR)
Y1361 Phosphorylation P06213 (INSR)
T1362 Phosphorylation
T1375 Phosphorylation
Site PTM Type Enzyme
S9 Phosphorylation
N51 N-Glycosylation
Y113 Phosphorylation
Y115 Phosphorylation
T123 Phosphorylation
Y131 Phosphorylation
N135 N-Glycosylation
N244 N-Glycosylation
N314 N-Glycosylation
T468 Phosphorylation
R471 Methylation
S473 Phosphorylation
R480 Methylation
S623 Phosphorylation
S624 Phosphorylation
K672 Ubiquitination
Y973 Phosphorylation P12931 (SRC) , P08069 (IGF1R)
Y980 Phosphorylation P08069 (IGF1R) , P12931 (SRC)
S982 Phosphorylation P08069 (IGF1R)
S1009 Phosphorylation
Y1014 Phosphorylation
K1033 Ubiquitination
K1055 Sumoylation
K1088 Acetylation
K1130 Sumoylation
K1150 Sumoylation
Y1161 Phosphorylation P12931 (SRC) , P08069 (IGF1R)
T1163 Phosphorylation
Y1165 Phosphorylation P12931 (SRC) , P08069 (IGF1R)
Y1166 Phosphorylation P08069 (IGF1R) , P12931 (SRC)
K1168 Ubiquitination
K1171 Ubiquitination
S1193 Phosphorylation
S1278 Phosphorylation P25098 (GRK2)
Y1280 Phosphorylation P08069 (IGF1R)
Y1281 Phosphorylation P08069 (IGF1R)
S1308 Phosphorylation
S1310 Phosphorylation
S1311 Phosphorylation
S1312 Phosphorylation
S1313 Phosphorylation
S1321 Phosphorylation P43250 (GRK6)
S1339 Phosphorylation
Y1346 Phosphorylation P08069 (IGF1R)
K1354 Methylation
S1364 Phosphorylation
T1366 Phosphorylation
C1367 S-Nitrosylation

PTMs - P08069/P06213 As Enzyme

Substrate Site Source
P06213 (INSR) Y992 Uniprot
P06213 (INSR) Y999 Uniprot
P06213 (INSR) Y1011 Uniprot
P06213-2 (INSR) Y1173 Uniprot
P06213-2 (INSR) Y1177 Uniprot
P06213-2 (INSR) Y1178 Uniprot
P06213 (INSR) Y1185 Uniprot
P06213 (INSR) Y1189 Uniprot
P06213 (INSR) Y1190 Uniprot
P06213-2 (INSR) S1302 Uniprot
P06213 (INSR) S1314 Uniprot
P06213 (INSR) S1332 Uniprot
P06213 (INSR) S1333 Uniprot
P06213-2 (INSR) S1336 Uniprot
P06213-2 (INSR) Y1343 Uniprot
P06213 (INSR) S1348 Uniprot
P06213-2 (INSR) Y1349 Uniprot
P06213 (INSR) Y1355 Uniprot
P06213 (INSR) Y1361 Uniprot
P07550 (ADRB2) Y132 Uniprot
P07550 (ADRB2) Y141 Uniprot
P07550 (ADRB2) Y350 Uniprot
P07550 (ADRB2) Y354 Uniprot
P0DP23 (CALM1) Y100 Uniprot
P0DP23 (CALM1) Y139 Uniprot
P15090 (FABP4) Y20 Uniprot
P18031 (PTPN1) Y66 Uniprot
P18031 (PTPN1) Y152 Uniprot
P18031 (PTPN1) Y153 Uniprot
P22681 (CBL) Y371 Uniprot
P22681 (CBL) Y700 Uniprot
P25963 (NFKBIA) Y42 Uniprot
P27986-3 (PIK3R1) Y68 Uniprot
P27986-2 (PIK3R1) Y98 Uniprot
P27986-3 (PIK3R1) Y280 Uniprot
P27986-3 (PIK3R1) Y307 Uniprot
P27986-2 (PIK3R1) Y310 Uniprot
P27986-2 (PIK3R1) Y337 Uniprot
P27986 (PIK3R1) Y368 Uniprot
P27986 (PIK3R1) Y580 Uniprot
P27986-1 (PIK3R1) Y607 Uniprot
P29350 (PTPN6) Y536 Uniprot
P29350-3 (PTPN6) Y538 Uniprot
P29353-7 (SHC1) Y318 Uniprot
P29353-1 (SHC1) Y427 Uniprot
P35232 (PHB) Y114 Uniprot
P35568 (IRS1) Y896 Uniprot
P35568 (IRS1) Y989 Uniprot
P35568 (IRS1) Y1179 Uniprot
P35568 (IRS1) Y1229 Uniprot
P42229 (STAT5A) Y694 Uniprot
P51692 (STAT5B) Y699 Uniprot
P53004 (BLVRA) Y198 Uniprot
P53004 (BLVRA) Y228 Uniprot
P53004 (BLVRA) Y291 Uniprot
P60484 (PTEN) Y27 Uniprot
P60484 (PTEN) Y174 Uniprot
P67775 (PPP2CA) Y307 Uniprot
Q05397-1 (PTK2) Y576 Uniprot
Q05397-1 (PTK2) Y577 Uniprot
Q13017 (ARHGAP5) Y306 Uniprot
Q13480 (GAB1) Y242 Uniprot
Q13480-2 (GAB1) Y285 Uniprot
Q13480-1 (GAB1) Y373 Uniprot
Q13480 (GAB1) Y447 Uniprot
Q13480 (GAB1) Y472 Uniprot
Q13480 (GAB1) Y589 Uniprot
Q13480-2 (GAB1) Y619 Uniprot
Q13480-1 (GAB1) Y627 Uniprot
Q13480-2 (GAB1) Y657 Uniprot
Q13480-1 (GAB1) Y659 Uniprot
Q13480-2 (GAB1) Y689 Uniprot
Q658W2 (DKFZp666O0110) Y598 Uniprot
Q658W2 (DKFZp666O0110) Y599 Uniprot
Q92569 (PIK3R3) Y341 Uniprot
Q99704 (DOK1) Y362 Uniprot
Q99704 (DOK1) Y398 Uniprot
Q9Y4H2 (IRS2) Y628 Uniprot
Q9Y4H2 (IRS2) Y632 Uniprot
Substrate Site Source
O15530 (PDPK1) Y373 Uniprot
O15530 (PDPK1) Y376 Uniprot
P07550 (ADRB2) Y132 Uniprot
P07550 (ADRB2) Y141 Uniprot
P08069 (IGF1R) Y973 Uniprot
P08069 (IGF1R) Y980 Uniprot
P08069 (IGF1R) S982 Uniprot
P08069 (IGF1R) Y1161 Uniprot
P08069 (IGF1R) Y1165 Uniprot
P08069 (IGF1R) Y1166 Uniprot
P08069 (IGF1R) Y1280 Uniprot
P08069 (IGF1R) Y1281 Uniprot
P08069 (IGF1R) Y1346 Uniprot
P35568 (IRS1) Y465 Uniprot
P35568 (IRS1) Y612 Uniprot
P35568 (IRS1) Y632 Uniprot
P35568 (IRS1) Y662 Uniprot
P35568 (IRS1) Y732 Uniprot
P35568 (IRS1) Y896 Uniprot
P35568 (IRS1) Y941 Uniprot
P35568 (IRS1) Y989 Uniprot
P35568 (IRS1) Y1179 Uniprot
P35568 (IRS1) Y1229 Uniprot
P46108 (CRK) Y221 Uniprot
P78324 (SIRPA) Y470 Uniprot
P78324 (SIRPA) Y496 Uniprot

Research Backgrounds

Function:

Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R.

When present in a hybrid receptor with INSR, binds IGF1.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,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.

PTMs:

Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Autophosphorylation occurs in a sequential manner; Tyr-1165 is predominantly phosphorylated first, followed by phosphorylation of Tyr-1161 and Tyr-1166. While every single phosphorylation increases kinase activity, all three tyrosine residues in the kinase activation loop (Tyr-1165, Tyr-1161 and Tyr-1166) have to be phosphorylated for optimal activity. Can be autophosphorylated at additional tyrosine residues (in vitro). Autophosphorylated is followed by phosphorylation of juxtamembrane tyrosines and C-terminal serines. Phosphorylation of Tyr-980 is required for IRS1- and SHC1-binding. Phosphorylation of Ser-1278 by GSK-3beta restrains kinase activity and promotes cell surface expression, it requires a priming phosphorylation at Ser-1282. Dephosphorylated by PTPN1 (By similarity).

Polyubiquitinated at Lys-1168 and Lys-1171 through both 'Lys-48' and 'Lys-29' linkages, promoting receptor endocytosis and subsequent degradation by the proteasome. Ubiquitination is facilitated by pre-existing phosphorylation.

Sumoylated with SUMO1.

Controlled by regulated intramembrane proteolysis (RIP). Undergoes metalloprotease-dependent constitutive ectodomain shedding to produce a membrane-anchored 52 kDa C-Terminal fragment which is further processed by presenilin gamma-secretase to yield an intracellular 50 kDa fragment.

Subcellular Location:

Cell membrane>Single-pass type I membrane protein.

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionSubcellular location
Tissue Specificity:

Found as a hybrid receptor with INSR in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Expressed in a variety of tissues. Overexpressed in tumors, including melanomas, cancers of the colon, pancreas prostate and kidney.

Subunit 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 chain carries the kinase domain. Interacts with PIK3R1 and with the PTB/PID domains of IRS1 and SHC1 in vitro when autophosphorylated on tyrosine residues. Forms a hybrid receptor with INSR, 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 ARRB1 and ARRB2. Interacts with GRB10. Interacts with RACK1. Interacts with SOCS1, SOCS2 and SOCS3. Interacts with 14-3-3 proteins. Interacts with NMD2. Interacts with MAP3K5. Interacts with STAT3. Found in a ternary complex with IGF1 and ITGAV:ITGB3 or ITGA6:ITGB4. Interacts (nascent precursor form) with ZFAND2B.

Family&Domains:

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.

Function:

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.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,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).

PTMs:

After being transported from the endoplasmic reticulum to the Golgi apparatus, the single glycosylated precursor is further glycosylated and then cleaved, followed by its transport to the plasma membrane.

Autophosphorylated on tyrosine residues in response to insulin. Phosphorylation of Tyr-999 is required for binding to IRS1, SHC1 and STAT5B. Dephosphorylated by PTPRE at Tyr-999, Tyr-1185, Tyr-1189 and Tyr-1190. Dephosphorylated by PTPRF and PTPN1. Dephosphorylated by PTPN2; down-regulates insulin-induced signaling.

Subcellular Location:

Cell membrane>Single-pass type I membrane protein. Late endosome. Lysosome.
Note: Binding of insulin to INSR induces internalization and lysosomal degradation of the receptor, a means for downregulating this signaling pathway after stimulation. In the presence of SORL1, internalized INSR molecules are redirected back to the cell surface, thereby preventing their lysosomal catabolism and strengthening insulin signal reception.

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionSubcellular location
Tissue Specificity:

Isoform Long and isoform Short are predominantly expressed in tissue targets of insulin metabolic effects: liver, adipose tissue and skeletal muscle but are also expressed in the peripheral nerve, kidney, pulmonary alveoli, pancreatic acini, placenta vascular endothelium, fibroblasts, monocytes, granulocytes, erythrocytes and skin. Isoform Short is preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney. Found as a hybrid receptor with IGF1R in muscle, heart, kidney, adipose tissue, skeletal muscle, hepatoma, fibroblasts, spleen and placenta (at protein level). Overexpressed in several tumors, including breast, colon, lung, ovary, and thyroid carcinomas.

Subunit Structure:

Tetramer of 2 alpha and 2 beta chains linked by disulfide bonds. The alpha chains carry the insulin-binding regions, while the beta chains carry the kinase domain. 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 SORBS1 but dissociates from it following insulin stimulation. Binds SH2B2. Activated form of INSR interacts (via Tyr-999) with the PTB/PID domains of IRS1 and SHC1. The sequences surrounding the phosphorylated NPXY motif contribute differentially to either IRS1 or SHC1 recognition. Interacts (via tyrosines in the C-terminus) with IRS2 (via PTB domain and 591-786 AA); the 591-786 would be the primary anchor of IRS2 to INSR while the PTB domain would have a stabilizing action on the interaction with INSR. Interacts with the SH2 domains of the 85 kDa regulatory subunit of PI3K (PIK3R1) in vitro, when autophosphorylated on tyrosine residues. Interacts with SOCS7. Interacts (via the phosphorylated Tyr-999), with SOCS3. Interacts (via the phosphorylated Tyr-1185, Tyr-1189, Tyr-1190) with SOCS1. Interacts with CAV2 (tyrosine-phosphorylated form); the interaction is increased with 'Tyr-27'phosphorylation of CAV2 (By similarity). 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. Interacts with GRB7. Interacts with PDPK1. Interacts (via Tyr-1190) with GRB14 (via BPS domain); this interaction protects the tyrosines in the activation loop from dephosphorylation, but promotes dephosphorylation of Tyr-999, this results in decreased interaction with, and phosphorylation of, IRS1. Interacts (via subunit alpha) with ENPP1 (via 485-599 AA); this interaction blocks autophosphorylation. Interacts with PTPRE; this interaction is dependent of Tyr-1185, Tyr-1189 and Tyr-1190 of the INSR. Interacts with STAT5B (via SH2 domain). Interacts with PTPRF. Interacts with ATIC; ATIC together with PRKAA2/AMPK2 and HACD3/PTPLAD1 is proposed to be part of a signaling netwok regulating INSR autophosphorylation and endocytosis (By similarity). Interacts with the cone snail venom insulin Con-Ins G1. Interacts with the insulin receptor SORL1; this interaction strongly increases its surface exposure, hence strengthens insulin signal reception. Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the INSR C-terminal region. Interacts with GNAI3; the interaction is probably mediated by CCDC88A/GIV.

Family&Domains:

The tetrameric insulin receptor binds insulin via non-identical regions from two alpha chains, primarily via the C-terminal region of the first INSR alpha chain. Residues from the leucine-rich N-terminus of the other INSR alpha chain also contribute to this insulin binding site. A secondary insulin-binding site is formed by residues at the junction of fibronectin type-III domain 1 and 2.

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.

Research Fields

· Cellular Processes > Cell growth and death > Oocyte meiosis.   (View pathway)

· Cellular Processes > Transport and catabolism > Autophagy - animal.   (View pathway)

· Cellular Processes > Transport and catabolism > Endocytosis.   (View pathway)

· Cellular Processes > Cellular community - eukaryotes > Focal adhesion.   (View pathway)

· Cellular Processes > Cellular community - eukaryotes > Adherens junction.   (View pathway)

· Cellular Processes > Cellular community - eukaryotes > Signaling pathways regulating pluripotency of stem cells.   (View pathway)

· Environmental Information Processing > Signal transduction > MAPK signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > Ras signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > Rap1 signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > cGMP-PKG signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > HIF-1 signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > FoxO signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > Phospholipase D signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > mTOR signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > PI3K-Akt signaling pathway.   (View pathway)

· Environmental Information Processing > Signal transduction > AMPK signaling pathway.   (View pathway)

· Human Diseases > Drug resistance: Antineoplastic > EGFR tyrosine kinase inhibitor resistance.

· Human Diseases > Drug resistance: Antineoplastic > Endocrine resistance.

· Human Diseases > Endocrine and metabolic diseases > Type II diabetes mellitus.

· Human Diseases > Endocrine and metabolic diseases > Insulin resistance.

· Human Diseases > Endocrine and metabolic diseases > Non-alcoholic fatty liver disease (NAFLD).

· Human Diseases > Cancers: Overview > Pathways in cancer.   (View pathway)

· Human Diseases > Cancers: Overview > Transcriptional misregulation in cancer.

· Human Diseases > Cancers: Overview > Proteoglycans in cancer.

· Human Diseases > Cancers: Specific types > Glioma.   (View pathway)

· Human Diseases > Cancers: Specific types > Prostate cancer.   (View pathway)

· Human Diseases > Cancers: Specific types > Melanoma.   (View pathway)

· Human Diseases > Cancers: Specific types > Breast cancer.   (View pathway)

· Human Diseases > Cancers: Specific types > Hepatocellular carcinoma.   (View pathway)

· Organismal Systems > Aging > Longevity regulating pathway.   (View pathway)

· Organismal Systems > Aging > Longevity regulating pathway - multiple species.   (View pathway)

· Organismal Systems > Nervous system > Long-term depression.

· Organismal Systems > Endocrine system > Insulin signaling pathway.   (View pathway)

· Organismal Systems > Endocrine system > Ovarian steroidogenesis.

· Organismal Systems > Endocrine system > Progesterone-mediated oocyte maturation.

· Organismal Systems > Endocrine system > Regulation of lipolysis in adipocytes.

· Organismal Systems > Excretory system > Aldosterone-regulated sodium reabsorption.

References

1). Yang H et al. Activation of Hippocampal IR/IRS-1 Signaling Contributes to the Treatment with Zuogui Jiangtang Jieyu Decoction on the Diabetes-Related Depression. Evid Based Complement Alternat Med 2021 Jun 3;2021:6688723. (PubMed: 34149862)

Application: WB    Species: Rat    Sample: hippocampus tissue

Figure 3 ZJJ activated the hippocampal insulin signaling pathway in diabetic rats. (a) Bands of p-IR, IR, p-IRS-1, IRS-1, p-PI3K, PI3K, p-AKT, AKT, and GAPDH. (b–e) Both doses of ZJJ treatment increased the expression of p-IR (b), while the high dose of ZJJ treatment increased the expression of p-IRS-1 (c), p-PI3K (d), and p-AKT (e) in diabetic rats. n = 6 in each group. ##P < 0.01 and ##P < 0.05 vs. the control group. ∗∗P < 0.01 and ∗P < 0.05 vs. the DM group. Data are presented as the mean ± SEM.

Application: IF/ICC    Species: Rat    Sample: hippocampus tissue

Figure 4 ZJJ activated the neuronal insulin signaling pathway in diabetic rats. (a) Immunofluorescence analysis of p-IR, p-IRS-1, p-PI3K, and p-AKT. (b–e) Both doses of ZJJ treatment increased the immunopositivity of p-IR (b), while the high dose of ZJJ treatment increased the expression of p-IRS-1 (c), p-PI3K (d), and p-AKT (e) in the hippocampus of diabetic rats. n = 5 in each group. Bar = 50 μm. ##P < 0.01 vs. the control group. ∗∗P < 0.01 and ∗P < 0.05 vs. the DM group. Data are presented as the mean ± SEM.

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