| Structural highlights
Disease
[IGF1R_HUMAN] Defects in IGF1R are a cause of insulin-like growth factor 1 resistance (IGF1RES) [MIM:270450]. It is a disorder characterized by intrauterine growth retardation and poor postnatal growth accompanied with increased plasma IGF1.[1] [2]
Function
[IGF1R_HUMAN] 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.[3] [4] [5] [6] [7] [8] [9] [10] [11] When present in a hybrid receptor with INSR, binds IGF1. PubMed:12138094 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, PubMed:16831875 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.[12] [13] [14] [15] [16] [17] [18] [19] [20]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The crystal structure of the wild-type unactivated kinase domain (IGFRK-0P) of insulin-like growth factor-1 receptor has been reported previously at 2.7 A resolution [Munshi et al. (2002), J. Biol. Chem. 277, 38797-38802]. In order to obtain a high-resolution structure, a number of variants of IGFRK-0P were prepared and screened for crystallization. A double mutant with E1067A and E1069A substitutions within the kinase-insert region resulted in crystals that diffracted to 1.5 A resolution. Overall, the structure of the mutant IGFRK-0P is similar to that of the wild-type IGFRK-0P structure, with the exception of the previously disordered kinase-insert region in the wild type having become fixed. In addition, amino-acid residues 947-952 at the N-terminus are well defined in the mutant structure. The monomeric protein structure is folded into two lobes connected by a hinge region, with the catalytic center situated at the interface of the two lobes. Two molecules of IGFRK-0P in the asymmetric unit are associated as a dimer and two different types of dimers with their ATP-binding clefts either facing towards or away from each other are observed. The current refined model consists of a dimer and 635 water molecules.
Structure of apo, unactivated insulin-like growth factor-1 receptor kinase at 1.5 A resolution.,Munshi S, Hall DL, Kornienko M, Darke PL, Kuo LC Acta Crystallogr D Biol Crystallogr. 2003 Oct;59(Pt 10):1725-30. Epub 2003, Sep 19. PMID:14501110[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003 Dec 4;349(23):2211-22. PMID:14657428 doi:10.1056/NEJMoa010107
- ↑ Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, Ohtsuka Y, Hisatome I, Ninomoya H, Nanba E, Fukushima T, Takahashi S. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. 2005 Aug;90(8):4679-87. Epub 2005 May 31. PMID:15928254 doi:jc.2004-1947
- ↑ Kasuya J, Paz IB, Maddux BA, Goldfine ID, Hefta SA, Fujita-Yamaguchi Y. Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry. 1993 Dec 14;32(49):13531-6. PMID:8257688
- ↑ Tollefsen SE, Stoszek RM, Thompson K. Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation. Biochemistry. 1991 Jan 8;30(1):48-54. PMID:1846292
- ↑ Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem J. 1993 Mar 1;290 ( Pt 2):419-26. PMID:8452530
- ↑ Kato H, Faria TN, Stannard B, Roberts CT Jr, LeRoith D. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). J Biol Chem. 1993 Feb 5;268(4):2655-61. PMID:7679099
- ↑ Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999 Nov 25;253(1):1-6. PMID:10579905 doi:10.1006/excr.1999.4667
- ↑ Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000 May 19;275(20):15099-105. PMID:10747872 doi:10.1074/jbc.M000089200
- ↑ Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002 Oct 18;277(42):39684-95. Epub 2002 Jul 22. PMID:12138094 doi:10.1074/jbc.M202766200
- ↑ Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). J Biol Chem. 2003 Apr 11;278(15):13325-32. Epub 2003 Jan 28. PMID:12556535 doi:10.1074/jbc.M211398200
- ↑ Slaaby R, Schaffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, Brandt J. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem. 2006 Sep 8;281(36):25869-74. Epub 2006 Jul 10. PMID:16831875 doi:10.1074/jbc.M605189200
- ↑ Kasuya J, Paz IB, Maddux BA, Goldfine ID, Hefta SA, Fujita-Yamaguchi Y. Characterization of human placental insulin-like growth factor-I/insulin hybrid receptors by protein microsequencing and purification. Biochemistry. 1993 Dec 14;32(49):13531-6. PMID:8257688
- ↑ Tollefsen SE, Stoszek RM, Thompson K. Interaction of the alpha beta dimers of the insulin-like growth factor I receptor is required for receptor autophosphorylation. Biochemistry. 1991 Jan 8;30(1):48-54. PMID:1846292
- ↑ Soos MA, Field CE, Siddle K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem J. 1993 Mar 1;290 ( Pt 2):419-26. PMID:8452530
- ↑ Kato H, Faria TN, Stannard B, Roberts CT Jr, LeRoith D. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). J Biol Chem. 1993 Feb 5;268(4):2655-61. PMID:7679099
- ↑ Baserga R. The IGF-I receptor in cancer research. Exp Cell Res. 1999 Nov 25;253(1):1-6. PMID:10579905 doi:10.1006/excr.1999.4667
- ↑ Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB, Wang LH. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000 May 19;275(20):15099-105. PMID:10747872 doi:10.1074/jbc.M000089200
- ↑ Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A. Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem. 2002 Oct 18;277(42):39684-95. Epub 2002 Jul 22. PMID:12138094 doi:10.1074/jbc.M202766200
- ↑ Galvan V, Logvinova A, Sperandio S, Ichijo H, Bredesen DE. Type 1 insulin-like growth factor receptor (IGF-IR) signaling inhibits apoptosis signal-regulating kinase 1 (ASK1). J Biol Chem. 2003 Apr 11;278(15):13325-32. Epub 2003 Jan 28. PMID:12556535 doi:10.1074/jbc.M211398200
- ↑ Slaaby R, Schaffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, Brandt J. Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem. 2006 Sep 8;281(36):25869-74. Epub 2006 Jul 10. PMID:16831875 doi:10.1074/jbc.M605189200
- ↑ Munshi S, Hall DL, Kornienko M, Darke PL, Kuo LC. Structure of apo, unactivated insulin-like growth factor-1 receptor kinase at 1.5 A resolution. Acta Crystallogr D Biol Crystallogr. 2003 Oct;59(Pt 10):1725-30. Epub 2003, Sep 19. PMID:14501110
|
