- Advanced search
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
The circulating peptide hormones insulin (INS, P01308) and the related insulin-like growth factors (IGF) activate Class II receptor tyrosine kinases , to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post-translationally into two peptides, which then cross-link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post-translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably IRS1 (P35568), IRS2 (Q9Y4H2), SHC1 (P29353), GRB2 (P62993) and SOS1 (Q07889).
Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBP1-5, P08833, P18065, P17936, P22692, P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.
1. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]
2. Gable KL, Maddux BA, Penaranda C, Zavodovskaya M, Campbell MJ, Lobo M, Robinson L, Schow S, Kerner JA, Goldfine ID et al.. (2006) Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth. Mol. Cancer Ther., 5 (4): 1079-86. [PMID:16648580]
3. García-Echeverría C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R et al.. (2004) In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell, 5 (3): 231-9. [PMID:15050915]
4. Grassot J, Mouchiroud G, Perrière G. (2003) RTKdb: database of Receptor Tyrosine Kinase. Nucleic Acids Res., 31 (1): 353-8. [PMID:12520021]
5. Kurachi H, Jobo K, Ohta M, Kawasaki T, Itoh N. (1992) A new member of the insulin receptor family, insulin receptor-related receptor, is expressed preferentially in the kidney. Biochem. Biophys. Res. Commun., 187 (2): 934-9. [PMID:1530648]
6. MacDonald RG, Pfeffer SR, Coussens L, Tepper MA, Brocklebank CM, Mole JE, Anderson JK, Chen E, Czech MP, Ullrich A. (1988) A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science, 239 (4844): 1134-7. [PMID:2964083]
7. Párrizas M, Gazit A, Levitzki A, Wertheimer E, LeRoith D. (1997) Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins. Endocrinology, 138 (4): 1427-33. [PMID:9075698]
8. Sabbatini P, Korenchuk S, Rowand JL, Groy A, Liu Q, Leperi D, Atkins C, Dumble M, Yang J, Anderson K et al.. (2009) GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. Mol. Cancer Ther., 8 (10): 2811-20. [PMID:19825801]
9. Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, Beaulieu F, Chang C, Clarke W, Dell J et al.. (2005) Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J. Med. Chem., 48 (18): 5639-43. [PMID:16134929]
10. Wittman MD, Carboni JM, Yang Z, Lee FY, Antman M, Attar R, Balimane P, Chang C, Chen C, Discenza L et al.. (2009) Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem., 52 (23): 7360-3. [PMID:19778024]
Database page citation:
Type II RTKs: Insulin receptor family. Accessed on 27/04/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=321.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Catalytic receptors. Br J Pharmacol. 172: 5979-6023.