IGF Family (IGFs and Receptors)

Overview of Insulin-Like Growth Factors (IGFs)

IGFs (Insulin-like Growth Factors) belong to a class of insulin-like growth factors, comprising two low-molecular-weight polypeptides: IGF-I and IGF-II. Additionally, two types of specific receptors and six binding proteins are involved in IGF signaling. IGF-I is a heat-resistant, single-chain basic protein with 70 amino acids and a molecular weight of 7649 Da. On the other hand, IGF-II is a stable, single-chain weakly acidic protein with 67 amino acids and a molecular weight of 7471 Da, tolerating 0.1% SDS.

Both IGF-I and IGF-II exhibit more than 70% homology and share approximately 50% structural and functional similarity with human proinsulin. These polypeptide hormones, produced by the body's endocrine system, fulfill crucial roles in cell growth, differentiation, and metabolic regulation. The biological effects of IGFs are achieved by binding to specific receptors present on the surface of target cells. Upon binding, IGFs activate downstream signaling pathways, thereby influencing cellular functions.

Unlike other growth factors, IGFs predominantly exist as inactive complexes bound to specific binding proteins (BPs) in serum, extracellular fluid, or cell culture fluid.

IGF Receptors: Types and Binding Affinity

Two distinct IGF receptors have been identified: the IGF-I receptor and the IGF-II receptor, also known as the type I receptor and type II receptor, respectively. The structure of the IGF-I receptor closely resembles that of the insulin receptor (Ir). It consists of two subunits, α and β, which combine to form a glycoprotein α2β2 tetramer. The α subunit serves as the site for ligand binding, while the β subunit possesses internal tyrosine kinase activity, but lacks tyrosinase activity.

The binding affinity of IGFs and insulin (Ins) to the IGF receptors follows a specific pattern:

  • For the insulin receptor (Ir): Ins > IGF-I > IGF-II
  • For the IGF-I receptor: IGF-I > IGF-II > Ins
  • For the IGF-II receptor: IGF-II > IGF-I, and there is no cross-reaction with insulin.
Fig 1. IGF-2 and IGF-1 and their receptor binding specificity and affinity [3]
Fig 1. IGF-2 and IGF-1 and their receptor binding specificity and affinity [3]

IGF Signaling Pathway: Intricacies and IGFBP Influence

The IGFs (Insulin-like Growth Factors) signaling pathway is a complex network involved in mediating various biological effects. IGFs act as extracellular ligands, binding to receptors on the cell membrane through endocrine, autocrine, or paracrine mechanisms. These receptors include GF-IR, IGF-IR, insulin receptor, insulin-related receptors, and potentially others. Among them, IGF-IR plays a key role in mediating the biological effects of IGF-I and IGF-II, while GF-IR specifically binds to IGF-I. Notably, IGF-IR is the primary receptor responsible for transmitting signals, implying that the biological functions of IGFs are primarily realized through IGF-IR.

IGF-IR belongs to the tyrosine protein kinase family and is widely expressed on the surface of various cell types. It is composed of two α and two β subunits and acts as a transmembrane protein. Upon binding of free IGFs to IGF-IR, the receptor's β subunit undergoes tyrosine autophosphorylation, initiating the activation of multiple downstream signals. Current research focuses on two extensively studied pathways: the PI3K-Akt pathway and the Ras-MAPK pathway. These pathways play a role in stimulating cell proliferation and inhibiting apoptosis.

Influence of IGFBPs on Biological Activity

In the local cellular environment, IGFBPs (Insulin-like Growth Factor Binding Proteins) exert influence on the biological activity of IGFs. IGFBPs are present in the peripheral circulation and extracellular fluid, exhibiting strong binding affinity with IGFs. They transport IGFs, directing them to specific cells, and regulate their activity by extending the half-life of IGFs. Among the IGFBPs family, IGFBP-3 serves as the primary binding protein and is abundant in the bloodstream, with the majority of IGFs binding to it. Each protein within the IGFBPs family also interacts with multiple signaling pathways and demonstrates temporal and spatial specificity in expression.

Key Signaling Pathways

Several signaling pathways associated with IGFs have been extensively studied, including the IGFs-PI3K-PDK1-AKT/PKB pathway and the IGFs-Ras-Raf-MEK pathway. These pathways are closely linked to cell growth, cell cycle regulation, and cell death. However, specific regulatory mechanisms within these pathways require further exploration and research to deepen our understanding.

Fig 2. Ligands and receptors in the IGFs/insulin axis.
Fig 2. Ligands and receptors in the IGFs/insulin axis [4]

Clinical Significance of the IGF Family

The IGFs (Insulin-like Growth Factors) family holds significant clinical significance, encompassing IGF-1 and IGF-2, which play pivotal roles in cell proliferation, differentiation, and metabolic regulation.

1. Treatment of Growth and Development Disorders

IGF-1 plays a crucial role in children's growth and bone development. Individuals with growth disorders resulting from IGF-1 deficiency or IGF-1 receptor deficiency can benefit from exogenous IGF-1 therapy, which promotes normal growth and development.

2. Muscle Wasting Treatment

Muscle wasting is a common complication of various diseases and conditions, such as cancer, age-related decline, and chronic illnesses. Members of the IGFs family are involved in regulating muscle protein synthesis and cell proliferation. Hence, the application of IGFs or their analogs to stimulate muscle growth and prevent muscle atrophy holds promising clinical potential.

3. Osteoporosis Treatment

IGFs have a close relationship with bone health. They facilitate the proliferation and differentiation of bone cells and contribute to the growth and repair of bone tissue. Consequently, IGFs may serve as potential targets for treating osteoporosis and fractures.

4. Tumor Therapy

The IGFs family plays a crucial role in the initiation and progression of tumors. They participate in the growth, proliferation, and metastasis of tumor cells. As a result, IGFs and related pathways have become a significant focus in tumor therapy, involving the development of anti-tumor drugs and therapeutic strategies targeting IGFs.

The Role of IGFs in Disease and Beyond

The functions of IGFs (Insulin-like Growth Factors) extend beyond growth and development, encompassing a crucial role in the occurrence and progression of diseases. The aberrant IGF signaling pathway is implicated in various disorders, including growth disorders, muscle wasting, osteoporosis, diabetes, and tumors. IGFs interact with other growth factors, hormones, and cytokines to regulate processes such as cell growth, differentiation, and metabolism.

Investigations on IGFs offer valuable insights into biological development, regulation of cell growth, and disease mechanisms. Moreover, these studies present potential opportunities for the development of new therapeutic strategies and drugs. The exploration of IGFs and their related pathways has emerged as a vital area of research and treatment for a wide range of diseases, making significant contributions to advancing human health.

[1] Leroith, D. ,  Baserga, R. ,  Helman, L. , &  Roberts, C. T. . (1999). Insulin-like growth factors and cancer. British Journal of Cancer, 65(3), 218-223.
[2] Herbert, Y. , &  Thomas, R. . (2000). Role of the insulin-like growth factor family in cancer development and progression. Journal of the National Cancer Institute(18), 1472-89.
[3] van Beijnum, Judy R et al. “Insulin-like growth factor axis targeting in cancer and tumour angiogenesis - the missing link.” Biological reviews of the Cambridge Philosophical Society vol. 92,3 (2017): 1755-1768. doi:10.1111/brv.12306
[4] Whitney L. Stuard, Rossella Titone, Danielle M. Robertson. The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease. Front. Endocrinol., 2020.https://doi.org/10.3389/fendo.2020.00024.

Growth Factor Families

VEGF Family (VEGFs and Receptors)

The VEGF Family (VEGFs and Receptors) encompasses a group of growth factors and their corresponding receptors that play a crucial role in angiogenesis and vascular development.

VEGFs and Receptors Details
FGF Family (FGFs and Receptors)

The FGF family and its receptors (FGF receptors) play a significant role in cell growth, development, and tissue repair, making them essential components of the Growth Factors and Receptors landscape.

FGFs and Receptors Details
EGF Family (EGFs and Receptors)

The EGF Family (EGFs and Receptors) comprises growth factors and receptors that are key regulators of cell proliferation, tissue development, and wound healing.

EGFs and Receptors Details
IGF Family (IGFs and Receptors)

The IGF Family (IGFs and Receptors) consists of growth factors and receptors that play critical roles in promoting cell growth, differentiation, and metabolism regulation.

IGFs and Receptors Details
GDFs and Receptors

GDFs and Receptors represent a family of growth factors and receptors involved in diverse cellular processes, including embryonic development, tissue repair, and immune modulation.

GDFs and Receptors Details
PDGFs and Receptors

PDGFs and Receptors are growth factors and receptors that are essential for cell growth, tissue repair, and regulation of various physiological processes in the body.

PDGFs and Receptors