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Molecular Mechanisms of Insulin‐like Growth Factor I Receptor Function: Implications for Normal Physiology and Pathological States

Derek Leroith, Vicky A. Blakesley, Haim Werner

10.1002/cphy.cp070520

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Structural Aspects of Insulin‐Like Growth Factor Receptors
1.1 Structure of the Insulin‐Like Growth Factor I Receptor
1.2 Structure of the Insulin‐Like Growth Factor I Receptor Gene and mRNA
1.3 The Regulatory Region of the Insulin‐Like Growth Factor I Receptor Gene
2 Regulation of the Insulin‐Like Growth Factor I Receptor Gene
2.1 Transcriptional Regulation
2.2 Regulation by Growth Factors
2.3 Repression of the Insulin‐Like Growth Factor I Receptor by Tumor Suppressors
2.4 Developmental Regulation of the Insulin‐Like Growth Factor I Receptor
3 Heterogeneity of the Insulin‐Like Growth Factor I Receptor
3.1 Differences in Primary Structure
3.2 Additional Structural Heterogeneity
3.3 Hybrid Receptors
4 Function of the Insulin‐Like Growth Factor I Receptor
4.1 The Receptor and Signaling
4.2 The Insulin‐Like Growth Factor I Receptor and the Cell Cycle
4.3 The Insulin‐Like Growth Factor I Receptor and Apoptosis
4.4 Function as Assessed by Loss of the Insulin‐Like Growth Factor I Receptor: Studies of “Knock‐out” Mice
4.5 Human Genetic Short Stature
5 The Role of Insulin‐Like Growth Factor I Receptors in various Systems and Pathological States
5.1 Nervous System
5.2 Muscle
5.3 Reproductive System
5.4 Kidney
5.5 Immune System
5.6 Cancer
5.7 Effects of Insulin‐Like Growth Factor I on Gene Expression
6 Conclusion
Figure 1. Figure 1.

Schematic representation of subclasses of tyrosine kinase receptors. In Classes I and II, the extracellular ligand‐binding region has classic cysteine‐rich domains (CYS), whereas in Classes III and IV, it contains immunoglobulin domains. The cytoplasmic portion contains the highly conserved tyrosine kinase domain (TK), which in the case of Classes III and IV have a kinase insert region. PM = plasma membrane.
Figure 2. Figure 2.

Structures of the IGF‐I receptor gene and protein. The IGF‐I receptor gene comprises 21 exons. The IGF‐I receptor promoter consists of a region of about 500 bp of 5′ flanking region upstream of an “initiator” sequence (INR) which surrounds the single transcription start site. The 5′ UTR is almost 1 kb, and both the 5′ flanking region and 5′ UTR are extremely GC‐rich. The precursor protein has a signal peptide which is cleaved off in the endoplasmic reticulum and a proteolyic cleavage site which separates the α and the β subunits.
Figure 3. Figure 3.

Regulation of IGF‐I receptor gene expression.
Figure 4. Figure 4.

Regulation of the IGF system by WT1.
Figure 5. Figure 5.

Structures of the IGF receptor family. In addition to the insulin and IGF‐I receptors, the family includes an insulin receptor‐related receptor (IRR), hybrid receptors and the IGF‐II/mannose‐6‐phosphate receptor. The latter does not contain intrinsic tyrosine kinase activity.
Figure 6. Figure 6.

Schematic representation of intracellular signaling pathways emanating from the IGF‐I receptor. The activated IGF‐I receptor phosphorylates a number of adaptor proteins including IRS‐1, IRS‐2, SHC and Crk‐II. These tyrosine phosphoproteins then interact with downstream molecules, for example p85, Syp, Grb2 and Nck via their SH2 domains, thereby activating the Ras/Raf/MAP kinase, the PI3′‐kinase, and other kinase pathways.


Figure 1.

Schematic representation of subclasses of tyrosine kinase receptors. In Classes I and II, the extracellular ligand‐binding region has classic cysteine‐rich domains (CYS), whereas in Classes III and IV, it contains immunoglobulin domains. The cytoplasmic portion contains the highly conserved tyrosine kinase domain (TK), which in the case of Classes III and IV have a kinase insert region. PM = plasma membrane.



Figure 2.

Structures of the IGF‐I receptor gene and protein. The IGF‐I receptor gene comprises 21 exons. The IGF‐I receptor promoter consists of a region of about 500 bp of 5′ flanking region upstream of an “initiator” sequence (INR) which surrounds the single transcription start site. The 5′ UTR is almost 1 kb, and both the 5′ flanking region and 5′ UTR are extremely GC‐rich. The precursor protein has a signal peptide which is cleaved off in the endoplasmic reticulum and a proteolyic cleavage site which separates the α and the β subunits.



Figure 3.

Regulation of IGF‐I receptor gene expression.



Figure 4.

Regulation of the IGF system by WT1.



Figure 5.

Structures of the IGF receptor family. In addition to the insulin and IGF‐I receptors, the family includes an insulin receptor‐related receptor (IRR), hybrid receptors and the IGF‐II/mannose‐6‐phosphate receptor. The latter does not contain intrinsic tyrosine kinase activity.



Figure 6.

Schematic representation of intracellular signaling pathways emanating from the IGF‐I receptor. The activated IGF‐I receptor phosphorylates a number of adaptor proteins including IRS‐1, IRS‐2, SHC and Crk‐II. These tyrosine phosphoproteins then interact with downstream molecules, for example p85, Syp, Grb2 and Nck via their SH2 domains, thereby activating the Ras/Raf/MAP kinase, the PI3′‐kinase, and other kinase pathways.

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Article Title: Molecular Mechanisms of Insulin‐like Growth Factor I Receptor Function: Implications for Normal Physiology and Pathological States
 

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Derek Leroith, Vicky A. Blakesley, Haim Werner. Molecular Mechanisms of Insulin‐like Growth Factor I Receptor Function: Implications for Normal Physiology and Pathological States. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 633-662. First published in print 1999. doi: 10.1002/cphy.cp070520