インスリン様増殖因子受容体
インスリン様増殖因子受容体
１型受容体はインスリン受容体によく似る。チロシンキナーゼドメインをもっている。IGF-1に親和性が高い。
２型受容体はIGF-2に親和性が高い。細胞外ドメインが大きく、細胞内にチロシンキナーゼドメインをもたない。リソソームのマンノース6-リン酸受容体と同じものである。
Insulin-like growth factor 1 receptor
EC=2.7.10.1
Alternative name(s):
Insulin-like growth factor I receptor
Short name=IGF-I receptor
CD_antigen=CD221
Cleaved into the following 2 chains:
Insulin-like growth factor 1 receptor alpha chain
Insulin-like growth factor 1 receptor beta chain
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. Ref.8 Ref.10 Ref.11 Ref.12 Ref.19 Ref.23 Ref.25 Ref.27 Ref.32
When present in a hybrid receptor with INSR, binds IGF1. Ref.25 shows that hybrid receptors composed of IGF1R and INSR isoform Longare 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 Shortare activated by IGF1, IGF2 and insulin. In contrast, Ref.32 shows that hybrid receptors composed of IGF1R and INSR isoform Longand hybrid receptors composed of IGF1R and INSR isoform Shorthave similar binding characteristics, both bind IGF1 and have a low affinity for insulin. Ref.8 Ref.10 Ref.11 Ref.12 Ref.19 Ref.23 Ref.25 Ref.27 Ref.32
Catalytic activity
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.12 Ref.41 Ref.45 Ref.47 Ref.48 Ref.49 Ref.50 Ref.51 Ref.53 Ref.54
Enzyme regulation
Activated by autophosphorylation at Tyr-1165, Tyr-1161 and Tyr-1166 on the kinase activation loop; phosphorylation at all three tyrosine residues is required for optimal kinase activity. Inhibited by MSC1609119A-1, BMS-754807, PQIP, benzimidazole pyridinone, isoquinolinedione, bis-azaindole, 3-cyanoquinoline, 2,4-bis-arylamino-1,3-pyrimidine, pyrrolopyrimidine, pyrrole-5-carboxaldehyde, picropodophyllin (PPP), tyrphostin derivatives. While most inhibitors bind to the ATP binding pocket, MSC1609119A-1 functions as allosteric inhibitor and binds close to the DFG motif and the activation loop. Ref.29 Ref.41 Ref.45 Ref.47 Ref.48 Ref.49 Ref.50 Ref.51 Ref.52 Ref.53 Ref.54
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 GNB2L1/RACK1. Interacts with SOCS1, SOCS2 and SOCS3. Interacts with 14-3-3 proteins. Interacts with NMD2. Interacts with MAP3K5. Interacts with STAT3. Ref.10 Ref.13 Ref.15 Ref.17 Ref.18 Ref.20 Ref.21 Ref.26 Ref.27 Ref.28 Ref.30 Ref.31 Ref.47
Subcellular location
Cell membrane; Single-pass type I membrane protein Ref.33.
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. Ref.9 Ref.14 Ref.16 Ref.24
Post-translational modification
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. Ref.10 Ref.12 Ref.22 Ref.41 Ref.42 Ref.46 Ref.47 Ref.48 Ref.52
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. Ref.37
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.
Involvement in disease
Insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]: A disorder characterized by intrauterine growth retardation, poor postnatal growth and increased plasma IGF1 levels.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.55 Ref.56
Sequence similarities
Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.
Contains 4 fibronectin type-III domains.
Contains 1 protein kinase domain.
Cation-independent mannose-6-phosphate receptor
Short name=CI Man-6-P receptor
Short name=CI-MPR
Short name=M6PR
Alternative name(s):
300 kDa mannose 6-phosphate receptor
Short name=MPR 300
Insulin-like growth factor 2 receptor
Insulin-like growth factor II receptor
Short name=IGF-II receptor
M6P/IGF2 receptor
Short name=M6P/IGF2R
CD_antigen=CD222
Function
Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex. This receptor also binds IGF2. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Ref.7
Subunit structure
Binds HA-I and HA-II plasma membrane adapters By similarity. Interacts with DPP4; the interaction is direct. Binds GGA1, GGA2 and GGA3. Ref.7 Ref.8
Subcellular location
Lysosome membrane; Single-pass type I membrane protein. Note: Colocalized with DPP4 in internalized cytoplasmic vesicles adjacent to the cell surface. Ref.7
Domain
Contains 15 repeating units of approximately 147 AA harboring four disulfide bonds each. The most highly conserved region within the repeat consists of a stretch of 13 AA that contains cysteines at both ends.
Sequence similarities
Belongs to the MRL1/IGF2R family.
Contains 1 fibronectin type-II domain.
