专肽生物_定制多肽合成服务_多肽合成定制服务_多肽合成厂家_多肽合成公司

胰岛素样生长因子(Insulin-Like Growth Factors, IGF)的定义

胰岛素样生长因子（IGF）-1和IGF-2是普遍表达的肽类，其序列与胰岛素具有同源性。

Insulin-like growth factors (IGF)-1 and IGF-2 are ubiquitously expressed peptides with sequence homology to insulin.

胰岛素样生长因子(Insulin-Like Growth Factors, IGF)的相关多肽

胰岛素样生长因子（IGFs）与细胞膜上的特定受体，即胰岛素样生长因子-I受体（IGF-IR）相互作用，且这种相互作用受一组特异性结合蛋白的调节。所有这些分子均被视为胰岛素样生长因子（IGF）家族的成员，该家族包括多肽配体胰岛素样生长因子-I（IGF-I）和胰岛素样生长因子-II（IGF-II）、两种细胞膜受体（即IGF-IR和IGF-IIR）以及六种胰岛素样生长因子结合蛋白（即IGFBP-1至IGFBP-6）。

IGFs interacts with a specific receptor on the cell membrane, namely, the IGF-I receptor (IGF-IR), and the interaction is regulated by a group of specific binding proteins. All of these molecules are considered to be members of the IGF family, which includes the polypeptide ligands IGF-I and IGF-II, two types of cell membrane receptors (i.e., IGF-IR and IGF-IIR), and six IGF-binding proteins (i.e., IGFBP-1 through IGFBP-6).

胰岛素样生长因子(Insulin-Like Growth Factors, IGF)的结构特征

IGFs

胰岛素样生长因子-I（IGF-I）和胰岛素样生长因子-II（IGF-II）是单链多肽。这两种分子的氨基酸序列有62%的同源性。它们在结构上还有其他相似之处，且结构类似于胰岛素原【1】。IGF-I由70个氨基酸残基组成，IGF-II由67个氨基酸残基组成，分为A和B域（类似于胰岛素）、C域（类似于胰岛素原的连接肽）和D域（胰岛素中不存在）。IGF-I和IGF-II中的三个链内二硫键已被证明位于与（胰岛素）原胰岛素中类似的位置【1】。

IGF-I and IGF-II are single-chain polypeptides. The two molecules have 62% homology in their amino acid sequences. The molecules share additional structural similarities, and their structures resemble the structure of proinsulin【1】. IGF I consists of 70 amino acid residues, IGF I1 of 67, grouped into domains A and B (similar to insulin), C (analogous to the connecting peptide of proinsulin) and D (not present in insulins). The three intrachain disulfide bridges in IGF 1 and I1 have shown to be located in analogous positions to those in (pro) insulin【1】.

IGFBPs

哺乳动物胰岛素样生长因子结合蛋白（IGFBPs）的一级结构似乎包含三个大小大致相当的不同结构域：保守的N端结构域、高度可变的中区结构域和保守的C端结构域。N端结构域在信号肽后包含80-93个氨基酸残基。前体肽中的16-20个半胱氨酸中有10-12个位于该结构域内。在IGFBP-1至-5中，这12个半胱氨酸完全保守，而在IGFBP-6中，12个半胱氨酸中有10个是不变的【2】。中区结构域的大小从55个氨基酸残基到95个氨基酸不等，将N端结构域与C端结构域分隔开。每个中区片段的氨基酸序列似乎对该蛋白质是独特的。C端结构域高度保守，在总共16-20个半胱氨酸中，有6个位于C端，并且是严格保守的【2】。

The primary structures of mammalian IGFBPs appear to contain three distinct domains of roughly equivalent sizes: the conserved N-terminal domain, the highly variable midregion, and the conserved C-terminal domain.N-terminal domain contains 80–93 amino acid residues after the signal. Ten to 12 of the 16–20 cysteines found in the prepeptides are located within this domain. In IGFBP-1 to -5, these 12 cysteines are fully conserved, whereas in IGFBP-6, 10 of the 12 cysteines are invariant【2】.Midregion ranging in size from 55 amino acid residues to 95 amino acids separates the N-terminal domain from the C-terminal domain. The amino acid sequence for each midsegment appears to be unique to the protein. C-terminal region are highly conserved and, 6 cysteines of the total 16–20 cysteines are found in the C terminus and are strictly conserved【2】.

IGF Receptors

胰岛素样生长因子受体I（IGF-IR）和胰岛素样生长因子受体II（IGF-IIR）都是糖蛋白，位于细胞膜上。IGF-IR是由两个相同的α亚基和两个相同的β亚基组成的四聚体。从结构上看，IGF-IR与胰岛素受体相似，两者之间有60%的同源性。IGF-IIR是单聚体。受体的细胞外结构域中有三个配体结合区，一个用于结合IGF-II，两个用于结合含有甘露糖-6-磷酸（M6P）的蛋白质，包括肾素、增殖素、甲状腺球蛋白和（转化生长因子β（TGF-β）的潜在形式【2】。

Both IGF-IR and IGF-IIR are glycoproteins and are located on the cell membrane. IGF-IR is a tetramer of two identical a-subunits and two identical ß-subunits. Structurally, IGF-IR resembles the insulin receptor, and there is 60% homology between them. IGF-IIR is monomeric. Three ligand-binding regions are found in the extracellular domain of the receptor, one for IGF-II binding and two for proteins containing mannose-6-phosphate (M6P), including renin, proliferin, thyroglobulin, and the latent form of (TGF)-ß transforming growth factor【2】.

胰岛素样生长因子(Insulin-Like Growth Factors, IGF)的作用机制

胰岛素样生长因子（IGFs）与胰岛素样生长因子受体（IGF-IR）结合会激活受体的酪氨酸激酶活性，从而引发一系列级联反应。目前已经确定了IGF-IR的两条不同信号转导通路。一条通路激活Ras蛋白、Raf蛋白和丝裂原活化蛋白激酶，另一条通路则涉及磷酸肌醇-3-激酶。IGF-IR参与细胞转化。体外实验表明，通过消除IGF-IR基因、抑制其表达或抑制其功能，从而从细胞膜上移除IGF-IR，可以消除细胞转化【3】。胰岛素样生长因子结合蛋白（IGFBPs）具有多种复杂功能。IGFBPs能够抑制或增强IGFs的作用，从而抑制或刺激细胞增殖。IGFBPs对IGFs的这些相反作用由结合蛋白的分子结构决定。当与IGFs结合时，IGFBPs发挥三个主要作用：1）运输IGFs，2）保护IGFs免受降解，3）调节IGFs与IGF-IR之间的相互作用。通常，IGFBPs对IGFs的结合亲和力高于IGF-IR；因此，IGFBPs与IGFs的结合会阻断IGFs与IGF-IR之间的相互作用，从而抑制IGF的作用。然而，IGFBPs与IGFs的结合也能保护IGFs免受蛋白酶降解，这种保护作用可通过增加IGFs在局部组织中的生物利用度来增强其作用【3】。

Binding of IGFs to IGF-IR activates the receptor's tyrosine kinase activity, which triggers a cascade of reactions. Two distinct signal transduction pathways have been identified for IGF-IR. One pathway activates Ras protein, Raf protein, and mitogen-activated protein kinase, and the other pathway involves phosphoinositol-3-kinase. IGF-IR is involved in cell transformation. In vitro experiments have shown that removal of IGF-IR from the cell membrane by eliminating the IGF-IR gene, by suppressing its expression, or by inhibiting its function can abolish cell transformation【3】. IGFBPs have multiple and complex functions. IGFBPs are able to inhibit or to enhance the action of IGFs, resulting in either suppression or stimulation of cell proliferation. These opposing effects of IGFBPs on IGFs are determined by the molecular structures of the binding proteins. When binding to IGFs, IGFBPs play three major roles: 1) transporting IGFs, 2) protecting IGFs from degradation, and 3) regulating the interaction between IGFs and IGF-IR. Normally, IGFBPs have higher binding affinity to IGFs than does IGF-IR; therefore, binding of IGFBPs to IGFs blocks the interaction between IGFs and IGF-IR and suppresses IGF action. However, binding of IGFBPs to IGFs also protects IGFs from proteolytic degradation, and that protection can enhance the action of IGFs by increasing their bioavailability in local tissue【3】.

胰岛素样生长因子(Insulin-Like Growth Factors, IGF)的功能

直接参与癌症——胰岛素样生长因子-I（IGF-I）和胰岛素样生长因子-II（IGF-II）是多种癌细胞系的强促有丝分裂剂。动物实验表明，IGF-I的过表达会增加某些组织中肿瘤发展的可能性。胰岛素样生长因子（IGFs）对癌细胞的作用是通过胰岛素样生长因子受体（IGF-IR）介导的。从细胞膜中消除IGF-IR、阻断IGFs与IGF-IR的相互作用或中断IGF-IR的信号转导通路，均可消除IGFs对癌细胞的促有丝分裂作用。IGF-IR在某些癌症中过表达，且其过表达与侵袭性肿瘤相关。最近的一项研究表明，胰岛素受体参与介导IGF-II对乳腺癌的作用。具有强转移倾向的癌细胞比转移能力低的癌细胞具有更高的IGF-II和IGF-IR表达。在癌症中，胰岛素样生长因子结合蛋白（IGFBPs）调节IGFs的作用。在大多数情况下，结合蛋白会抑制IGFs的促有丝分裂作用并促进细胞凋亡。研究表明，IGFBP-3在不与IGFs相互作用的情况下抑制了乳腺癌细胞的生长【4】。

Direct Involvement in Cancer - IGF-I and IGF-II are strong mitogens for a wide variety of cancer cell lines. Animal experiments indicate that overexpression of IGF-I increase the likelihood of tumor development in certain tissues. The effects of IGFs on cancer cells are mediated through IGF-IR. Eliminating IGF-IR from the cell membrane, blocking the interaction of IGFs with IGF-IR, or interrupting the signal transduction pathway of IGF-IR can abolish the mitogenic action of IGFs on cancer cells. IGF-IR is overexpressed in certain cancers, and its overexpression is associated with aggressive tumors. A recent study indicates that the insulin receptor is involved in mediating the actions of IGF-II on breast cancer. Cancer cells with a strong tendency to metastasize have higher expression of IGF-II and IGF-IR than those with a low ability to do so.In cancer, IGFBPs regulate the action of IGFs. In most situations, the binding proteins suppress the mitogenic action of IGFs and promote apoptosis. It has been shown that IGFBP-3 inhibited breast cancer cell growth without interacting with IGFs【4】.

胰岛素样生长因子I（IGF-I）保护并拯救海马神经元免受β-淀粉样蛋白和人类胰淀素诱导的毒性影响——胰岛素样生长因子（IGF-I和IGF-II）是众所周知的营养因子，其特异性受体在大脑中分布独特，尤其集中在海马结构中。IGF在海马区具有神经营养活性，而海马区是阿尔茨海默病中受严重影响的一个区域。有证据表明，β-淀粉样蛋白（aβ）衍生的肽可能在阿尔茨海默病中观察到的神经退行性过程中发挥重要作用，已有研究表明，IGF可对海马神经元提供神经保护，使其免受淀粉样蛋白衍生物的毒性影响【5】。

IGF I protects and rescues hippocampal neurons against ß-amyloid- and human amylin-induced toxicity - Insulin-like growth factors (IGF-I and IGF-II) are well known trophic factors and their specific receptors are uniquely distributed throughout the brain, being especially concentrated in the hippocampal formation. IGFs possess neurotrophic activities in the hippocampus, an area severely affected in Alzheimer disease. There is evidence that ß-amyloid (aß)-derived peptides likely play an important role in the neurodegenerative process observed in Alzheimer disease, it has been shown that IGFs can be neuroprotective to hippocampal neurons against toxicity induced by amyloidogenic derivatives【5】.

胰岛素样生长因子(Insulin-Like Growth Factors, IGF)的相关文献

1.     Daughaday WH, Rotwein P (1989). Insulin-like growth factors I and II - Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr. Rev, 10:68–91.

2.     Jones JI, Clemmons DR (1995). Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev., 16:3–34.

3.     Clemmons DR (1997). Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev, 8:45–62.

4.     Yu H, Rohan T (2000). Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression. Journal of the National Cancer Institute., 92 (18):1472-1489.

5.     Doré S, Kar S, Quirion R (1997). Insulin-like growth factor I protects and rescues hippocampal neurons against ß-amyloid- and human amylin-induced toxicity. Proc. Natl. Acad. Sci, 94:4772–4777.

Cornish, J. et al. Am. J. Physiol. Endocrinol. Metab. 292, E117 (2007).