Insulin Like Growth Factors Insulin IGFs 1 and

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and Relaxin stimulate DNA synthesis and cell growth. All four growth factors are disulfide-linked heterodimers that are generated from precursor forms by proteolytic cleavage.

- Insulin is produced as proinsulin [Steiner and Oyer 1967] by the P cells of the islets of Langerhans in the pancreas.

- IGF-1 is mainly secreted by the liver and smooth muscle cells as a result of stimulation by growth hormone. Most cells are responsive to IGF-1, especially cells in muscle, cartilage, bone, liver, kidney, nerves, skin, and lungs. A large fraction of the circulating IGF-1 is attached to IGF-binding proteins (IGF-BPs).

- IGF-2 is secreted from fetal liver and placenta and from adult brain, kidney, pancreas, and muscle. It is more specific in action than IGF-1.

- Relaxin is a peptide hormone produced by the corpora lutea of ovaries during pregnancy. The secretion of the hormone into the blood stream just before parturition results in softening and lengthening of the pubic symphysis and a softening of the cervix, which facilitates the birth process. By inhibiting uterine contractions, Relaxin may influence the timing of parturition. The factor consists of two peptide chains covalently linked by disulfide bonds.

IGFs (Somatomedins) are expressed in two types, IGF-1 (Somatomedin C) and IGF-2 (Somatomedin A, Multiplication-Stimulating Factor, MSF). They are bound to carrier proteins and are maintained at relatively steady serum levels. While IGF-2 is a primary growth factor required for early development, IGF-1 expression mostly occurs in later life.

The mature Insulin Receptor is derived from precursor polypeptides. It consists of two a subunits (1,370 amino acids or 1,382 amino acids, generated by alternative splicing) and two P subunits (624 amino acids). The a subunits are extracellular, while the P subunits traverse the membrane and possess tyrosine kinase activity. The proto-oncogene ros encodes the Insulin Receptor P chain. Although several receptors for IGFs exist, the biological actions of IGF-1 and IGF-2 are predominantly exerted through the type-1 IGF-1R, which binds IGF-1 and IGF-2 with high affinity. Activation of the IGF-1R occurs following IGF-1 binding to the a subunit of the IGF-1R on epithelial cells, leading to autophosphorylation of the P subunit. The IGF-1R displays potent mitogenic, antiapoptotic, and transforming activities, which may be a prerequisite for oncogenesis. IGF-1R is a heterotetrameric tyrosine kinase receptor, closely related to Insulin Receptor in sequence and structure. It is linked to the RAS^RAF^MAPK and to the PI 3-K^PKB signal transduction cascades. In contrast, IGF-2R is a single polypeptide chain with a short cytoplasmic tail that lacks kinase activity. IGF signaling supports cell proliferation in several ways (Figure 3.1.3.F).

- Engagement of the Insulin Receptor by Insulin stimulates the phosphorylation of the Insulin Receptor Substrates (IRS) -1, -2, and -3. These proteins associate with the regulatory subunit, P85, of Phosphatidylinositol 3-Kinase and activate it, which in turn mediates the activation of PKB-2 (AKT-2). PKB plays a central role in glucose uptake and glycogen synthesis.

- IGF-1 may signal to prevent apoptosis through RAS, Phosphatidylinositol 3-Kinase, and PKB (AKT Kinase), ultimately impacting on BAD, a key modulator of the BCL-2 family. mTOR (Mammalian Target of Rapamycin) is a serine/ threonine kinase and a substrate for PKB, which plays a critical role in promoting cell survival.

- Receptor ligation by IGFs rapidly activates nuclear PLCP1, which in conjunction with the phosphatidylinositol pathway contributes to the control of mRNA export from the nucleus and is essential for the mitogenic effect of IGF [York et al. 1999].

The biological actions of IGF are mediated primarily by its association with the type-1 IGF-1R, which is regulated by a group of high affinity IGFBP-1 through IGFBP-6. The IGF-BPs have growth inhibitory effects by competitively binding IGFs and preventing their association with the IGF-1R. All IGF-BPs have 16-18 conserved cysteine residues in the NH2- and COOH-terminal regions. IGF-BP3 is the most abundant binding protein in the circulation

IRb IRa IGF1R IGF1R IGF1R TNFctR

IRb IRa IGF1R IGF1R IGF1R TNFctR

Vertebrate And Invertebrate

Degradation

Figure 3.1.3.F. Insulin and IGF signaling. Insulin and IGF-1 (Insulin-Like Growth Factor 1) Receptors form hybrids that modulate the selectivity and affinity for Insulin, IGF-1, and IGF-2. Insulin or IGF binding stimulates tyrosine autophosphorylation in the receptor p subunits, which activates the kinase and recruits the cellular substrates IRS-1 and IRS-2 for tyrosine phosphorylation. This recruitment is regulated by serine phosphorylation of the IRS proteins, which inhibits the interaction between their PTB domains and the phospho-rylated receptor. Proinflammatory cytokines increase the synthesis of SOCS-1 or SOCS-3, which promote the ubiquitination and degradation of IRS-1 and IRS-2. cAMP synthesis enhances the expression of IRS-2 through the activity of phosphorylated CREB. Tyrosine phosphorylation of IRS-1 or IRS-2 recruits and activates various SH2 domain-containing proteins, including PI 3-Kinase, which activates the PKB cascade. pY = phosphotyrosine, pS = phosphoserine, PKC%/Z = Protein Kinase C % or Z, E2 = Ubiquitin conjugating enzymes, TNFaR = Tumor Necrosis Factor a Receptor, GLP-1R = Glucagon-Like Peptide-1 Receptor, IL6R = Interleukin-6 Receptor. [Reproduced from White 2003. With permission.]

Degradation

Figure 3.1.3.F. Insulin and IGF signaling. Insulin and IGF-1 (Insulin-Like Growth Factor 1) Receptors form hybrids that modulate the selectivity and affinity for Insulin, IGF-1, and IGF-2. Insulin or IGF binding stimulates tyrosine autophosphorylation in the receptor p subunits, which activates the kinase and recruits the cellular substrates IRS-1 and IRS-2 for tyrosine phosphorylation. This recruitment is regulated by serine phosphorylation of the IRS proteins, which inhibits the interaction between their PTB domains and the phospho-rylated receptor. Proinflammatory cytokines increase the synthesis of SOCS-1 or SOCS-3, which promote the ubiquitination and degradation of IRS-1 and IRS-2. cAMP synthesis enhances the expression of IRS-2 through the activity of phosphorylated CREB. Tyrosine phosphorylation of IRS-1 or IRS-2 recruits and activates various SH2 domain-containing proteins, including PI 3-Kinase, which activates the PKB cascade. pY = phosphotyrosine, pS = phosphoserine, PKC%/Z = Protein Kinase C % or Z, E2 = Ubiquitin conjugating enzymes, TNFaR = Tumor Necrosis Factor a Receptor, GLP-1R = Glucagon-Like Peptide-1 Receptor, IL6R = Interleukin-6 Receptor. [Reproduced from White 2003. With permission.]

and controls the actions of the IGFs by regulating their distribution and bioavailability to target tissues.

• IGF-1 may act as an autocrine growth factor in neuroendocrine tumor cells. In carcinoid tumor cells, IGF-1 stimulates Phosphatidylinositol 3-Kinase, P70 S6 Kinase, and ERK-2. Melanoma cells do not respond to growth stimulation by IGF-1 because of a constitutive activation of the MAP Kinase pathway [Satyamoorthy et al. 2001].

• Stromal-epithelial interactions are vital for full mammary gland development. IGFs are synthesized by stromal cells of the mammary connective tissue. IGF-1 and IGF-2 are potent mitogens and survival factors for breast epithelial cells. They act primarily through the IGF-1R, which is significantly overex-pressed and highly activated in breast tumors.

• In sporadic cases of Wilms tumor, the expression of the igf-2 gene is markedly increased relative to the surrounding tissue or to adult kidneys, but is comparable to the level of expression in several fetal tissues including kidney, liver, adrenal, and striated muscle [Reeve et al. 1985; Scott et al. 1985].

• IGF-2 is a modulator of muscle growth and differentiation. Its gene is widely expressed during prenatal development and is regulated by genomic imprinting (inactivation of the maternal copy). While this leads to monoallelic expression of igf-2 in normal adult muscle tissue, two or more copies of active igf-2 alleles are associated with rhab-domyosarcoma, arising either by relaxation of imprinting or by duplication of the active allele. IGF-2 acts as an autocrine growth factor for rhab-domyosarcoma cells, and its elevated expression may be an important step for the initiation or progression of rhabdomyosarcoma. The loss of imprinting (LOI) of igf-2 is associated with all his-tologic subtypes of rhabdomyosarcoma, but not with leiomyosarcoma [Pedone et al. 1994].

• Glucocorticosteroids counteract the effects of Insulin and suppress the growth of certain tumors [Osborne etal. 1979].

• The proto-oncogene ros (mcf-3) encodes the Insulin Receptor p chain, which acts as a protein tyrosine kinase receptor. It is highly expressed in glioblastomata. In some glioblastomata, an interstitial deletion of 240 kb on 6q21 fuses the fig gene to the ros1 gene. The resulting ROS1-FIG fusion protein is a constitutively activated tyrosine kinase [Charest et al. 2003a,b]. • ros1 is located on chromosome 6q22. Chromosomal rearrangements in the 6q11-q31 region are associated with acute lymphoblastic leukemia (ALL), malignant melanoma, and ovarian carcinoma. They may reflect a role for ros1 in transformation.

Hepatocyte Growth Factor. Hepatocyte Growth Factor (HGF, Scatter Factor) is encoded by a single transcript, whose 728 amino acid product is processed by proteolytic cleavage into a 87 kD disulfide-linked heterodimer of a heavy chain and a light chain. HGF contains a serine protease-like domain (with critical histidine and serine residues mutated) and Kringle domains. Under physiologic conditions, HGF is not an autocrine, but rather a paracrine, factor. Mesenchymal cells produce HGF, which is mitogenic for melanocytes, renal tubular cells, and some epithelial cells.

The 145 kD proto-oncogene product and receptor tyrosine kinase c-MET acts as a receptor for HGF. The product of the met proto-oncogene {7q31}, MET, is a transmembrane protein, synthesized as a single chain precursor, which undergoes intracellular proteolytic cleavage at a basic amino acid site, yielding a disulfide-linked heterodimer. Its COOH-terminal, intracellular region contains a multifunctional docking site that binds to various signaling molecules. The MET receptor tyrosine kinase family consists of two related proteins, MET and RON. The extracellular regions of both MET and RON display structural similarities with Semaphorins and Plexins (Figure 3.1.3.G). The RON receptor tyrosine kinase recognizes Macrophage-Stimulating Protein (MSP) (Figure 3.1.3.H).

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