The Role of the IGF/Insulin-IGFBP Axis in Normal Physiology and Disease

Editorial

21 April 2022

Editorial: The Role of the IGF/Insulin-IGFBP Axis in Normal Physiology and Disease

Shin-Ichiro Takahashi

and

Claire M. Perks

1,690 views

3 citations

Editors

Claire Perks

University of Bristol

Shin-Ichiro Takahashi

The University of Tokyo

Impact

(A) The IGF-1R translocates to the Golgi apparatus. In migratory cell lines, IGF-1R autophosphorylates Tyr1250/1251 in an adhesion dependent manner. Phosphorylation of Tyr1250/1251 IGF-1R leads to rapid IGF-1R endocytosis leads to activation of the MAPK pathway and results in translocation of the IGF-1R to the Golgi which promotes sustained SHC activation to facilitate migration. points. The release and retention of IGF-1R in the Golgi may be regulated by β1-Integrin and its interaction with the ECM. In cells with low or no migratory capacity, IGF-1R remains on the surface inducing signaling from the membrane. The interaction with other proteins, including E-cadherin, stabilizes the adhesion points and internalization rate of the IGF-1R is low. (B) IGF-1R translocates to the nucleus. IGF-1 binding to the IGF-1R induces the translocation of the membrane receptor to the nucleus. Various mechanisms have been proposed for the import of the IGF-1R to the nucleus. Nuclear IGF-1R can bind to DNA and enhance or initiate the transcription of various genes, leading to cell survival, migration, EMT and cell cycle progression. (C) IGF-1 signaling regulates mitochondrial function. The activation of the PI3-K pathway in response to IGF-1 induces the expression of the mitophagy regulators PGC1β and PRC. Inhibition of GSK-3 β by PI3-K activation leads to the release of NFE2L2/Nrf2, which translocates to the nucleus to enhance the expression of the mitophagy receptor BNIP-3. Activation of IGF1-R also enhances the expression of the UTP importer PNC-1, which was linked to cell growth and the reduction of ROS. Through these pathways IGF-1 signaling contributes to the maintenance of mitochondrial homeostasis. Figure elements adapted from Servier Medical Art (https://smart.servier.com/), under license CC-BY3.0.

Mini Review

29 January 2021

Controlled Signaling—Insulin-Like Growth Factor Receptor Endocytosis and Presence at Intracellular Compartments

Leonie Rieger

and

Rosemary O’Connor

Ligand-induced activation of the IGF-1 receptor triggers plasma-membrane-derived signal transduction but also triggers receptor endocytosis, which was previously thought to limit signaling. However, it is becoming ever more clear that IGF-1R endocytosis and trafficking to specific subcellular locations can define specific signaling responses that are important for key biological processes in normal cells and cancer cells. In different cell types, specific cell adhesion receptors and associated proteins can regulate IGF-1R endocytosis and trafficking. Once internalized, the IGF-1R may be recycled, degraded or translocated to the intracellular membrane compartments of the Golgi apparatus or the nucleus. The IGF-1R is present in the Golgi apparatus of migratory cancer cells where its signaling contributes to aggressive cancer behaviors including cell migration. The IGF-1R is also found in the nucleus of certain cancer cells where it can regulate gene expression. Nuclear IGF-1R is associated with poor clinical outcomes. IGF-1R signaling has also been shown to support mitochondrial biogenesis and function, and IGF-1R inhibition causes mitochondrial dysfunction. How IGF-1R intracellular trafficking and compartmentalized signaling is controlled is still unknown. This is an important area for further study, particularly in cancer.

9,381 views

27 citations

The samples were obtained from MS patients with spasticity receiving treatment cycles of four intrathecal TCA applications. Total IGFBP activity is composed of IGFBP-2 and IGFBP-3. The plot depicts the average change in molar ratios over 20 treatment cycles (14 cycles in four males and 6 cycles in two females). Data are given as means ± SEM (*p < 0.05; ***p < 0.001).

Original Research

05 January 2021

Reduced Fragmentation of IGFBP-2 and IGFBP-3 as a Potential Mechanism for Decreased Ratio of IGF-II to IGFBPs in Cerebrospinal Fluid in Response to Repeated Intrathecal Administration of Triamcinolone Acetonide in Patients With Multiple Sclerosis

Andreas Hoeflich

, 5 more and

Uwe Klaus Zettl

2,742 views

4 citations

PI3K/Akt pathway in health (A), cancer (B) and AD brain (C) cells. This is a schematic of the PI3K/Akt cellular pathway which regulates cell proliferation, metabolism and death. These figures attempt to highlight possible differences in cancer and AD compared with health. These indicated differences, as described in human and animal tissues and in cell culture, are meant to represent general concepts not specific cases. (A) shows normal regulation (B) indicates a cancer phenotype (C) illustrates AD as an insulin-resistant state i.e., T3DM. Green lines represent activation and purple lines represent feedback from the activation pathway. Activation of the IGF-1/insulin receptors leads to tyrosine phosphorylation of IRS-1 and activation of mTORC2 and Akt, resulting in glucose uptake. Homeostasis is maintained partly by mTORC1 sensing of metabolic conditions, which, as appropriate, leads to phosphorylation of p53 and S6K1 serine phosphorylation of IRS-1. p53 is a negative regulator of IGF/insulin receptors, IGF-II and glucose transporters. [A] Normal cellular homeostasis as described above [B] In cancer, negative feedback pathways are switched off leading to upregulation of proliferation, metabolism and cell survival. A modified genetic landscape (e.g., p53, PTEN) enables tumor cells to benefit from a glucose-rich, IGF/insulin-rich environment (insulin-resistance such as in T2DM).In cancer, Akt can phosphorylate and inactivate GSK-3β, which results in increased protein synthesis that supports cell growth. [C] In AD brain with insulin-resistance, or if, due to decreased blood flow there is no glucose accessible, the PI3K/Akt pathway is effectively switched off or downregulated. This leads to upregulation of GSK-β that culminates in tau phosphorylation and aggregation and increased amyloid beta production. Lack of intraneuronal glucose would trigger AMPK to activate mTORC1, p53, S6K1 serine phosphorylation of IRS-1. This could be a self-perpetuating cycle.

Mini Review

23 June 2020

Mini Review: Opposing Pathologies in Cancer and Alzheimer's Disease: Does the PI3K/Akt Pathway Provide Clues?

Rachel M. Barker

, 3 more and

Claire M. Perks

6,933 views

20 citations

Knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 reduced the level of phospho-Erk and sensitized the cells to 4-OHT. (A) Immunoblot analysis of IGFBP-1, phospho-Erk, and Erk after transfected with non-targeting (NT) shRNA or IGFBP-1 shRNA in MCF7-BP1 (left); measurement of relative cell number (%) in MCF7-BP1 after transfected with NT shRNA or IGFBP-1 shRNA and treated with either vehicle or 1 μM 4-OHT (right). (B) Immunoblot analysis of IGFBP-1, phospho-Erk, and Erk after transfected with non-targeting (NT) shRNA or shRNA for IGFBP-1 in T47D-BP1 (left); measurement of relative cell number (%) in T47D-BP1 after transfected with NT shRNA or IGFBP-1 shRNA and treated with either vehicle or 1 μM 4-OHT (right). Results are the average of 3 independent experiments, and error bars are the standard error of the mean. *p < 0.05.

Original Research

06 May 2020

IGFBP-1 Expression Promotes Tamoxifen Resistance in Breast Cancer Cells via Erk Pathway Activation

Yan Zheng

, 1 more and

Kevin D. Houston

4,367 views

25 citations

Original Research

02 September 2020

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

Rikke Hjortebjerg

, 6 more and

Jan Frystyk

3,148 views

4 citations

Correction

28 August 2020

Corrigendum: Insulin-Like Growth Factor Binding Protein-5 in Physiology and Disease

Cunming Duan

and

John B. Allard

1,834 views

2 citations

Review

03 March 2020

The IGF/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease

Whitney L. Stuard

, 1 more and

Danielle M. Robertson

The insulin-like growth factor (IGF) family plays key roles in growth and development. In the cornea, IGF family members have been implicated in proliferation, differentiation, and migration, critical events that maintain a smooth refracting surface that is essential for vision. The IGF family is composed of multiple ligands, receptors, and ligand binding proteins. Expression of IGF type 1 receptor (IGF-1R), IGF type 2 receptor (IGF-2R), and insulin receptor (INSR) in the cornea has been well characterized, including the presence of the IGF-1R and INSR hybrid (Hybrid-R) in the corneal epithelium. Recent data also indicates that each of these receptors display unique intracellular localization. Thus, in addition to canonical ligand binding at the plasma membrane and the initiation of downstream signaling cascades, IGF-1R, INSR, and Hybrid-R also function to regulate mitochondrial stability and nuclear gene expression. IGF-1 and IGF-2, two of three principal ligands, are polypeptide growth factors that function in all cellular layers of the cornea. Unlike IGF-1 and IGF-2, the hormone insulin plays a unique role in the cornea, different from many other tissues in the body. In the corneal epithelium, insulin is not required for glucose uptake, due to constitutive activation of the glucose transporter, GLUT1. However, insulin is needed for the regulation of metabolism, circadian rhythm, autophagy, proliferation, and migration after wounding. There is conflicting evidence regarding expression of the six IGF-binding proteins (IGFBPs), which function primarily to sequester IGF ligands. Within the cornea, IGFBP-2 and IGFBP-3 have identified roles in tissue homeostasis. While IGFBP-3 regulates growth control and intracellular receptor localization in the corneal epithelium, both IGFBP-2 and IGFBP-3 function in corneal fibroblast differentiation and myofibroblast proliferation, key events in stromal wound healing. IGFBP-2 has also been linked to cellular overgrowth in pterygium. There is a clear role for IGF family members in regulating tissue homeostasis in the cornea. This review summarizes what is known regarding the function of IGF and related proteins in corneal development, during wound healing, and in the pathophysiology of disease. Finally, we highlight key areas of research that are in need of future study.

12,924 views

74 citations

Review

03 March 2020

Insulin-Like Growth Factor Binding Protein-5 in Physiology and Disease

Cunming Duan

and

John B. Allard

Insulin-like growth factor (IGF) signaling is regulated by a conserved family of IGF binding proteins (IGFBPs) in vertebrates. Among the six distinct types of IGFBPs, IGFBP-5 is the most highly conserved across species and has the broadest range of biological activities. IGFBP-5 is expressed in diverse cell types, and its expression level is regulated by a variety of signaling pathways in different contexts. IGFBP-5 can exert a range of biological actions including prolonging the half-life of IGFs in the circulation, inhibition of IGF signaling by competing with the IGF-1 receptor for ligand binding, concentrating IGFs in certain cells and tissues, and potentiation of IGF signaling by delivery of IGFs to the IGF-1 receptor. IGFBP-5 also has IGF-independent activities and is even detected in the nucleus. Its broad biological activities make IGFBP-5 an excellent representative for understanding IGFBP functions. Despite its evolutionary conservation and numerous biological activities, knockout of IGFBP-5 in mice produced only a negligible phenotype. Recent research has begun to explain this paradox by demonstrating cell type-specific and physiological/pathological context-dependent roles for IGFBP-5. In this review, we survey and discuss what is currently known about IGFBP-5 in normal physiology and human disease. Based on recent in vivo genetic evidence, we suggest that IGFBP-5 is a multifunctional protein with the ability to act as a molecular switch to conditionally regulate IGF signaling.

12,763 views

78 citations

Protein level of IRSs and cleaved caspase 3 during myogenic differentiation of L6 myoblasts. (A) Differentiation of L6 myoblasts was induced by changing media from DMEM with 10% FBS to DMEM with 2% FBS. At the indicated days after differentiation induction, cell lysates were prepared, and total cell lysates were produced for immunoblotting analysis using the indicated antibodies. (B) Differentiation was induced in the differentiation medium with or without 100 μM Z-VAD-FMK. Immunoblotting was conducted using the indicated antibodies at the indicated days after differentiation induction. (C) L6-mock, L6-GFP, and L6-GFP-IRS-1 were induced to differentiate into myotubes. Immunoblotting was conducted at the indicated days after differentiation induction. (D) At the indicated days after differentiation induction, cells were fixed by PFA and immunostained with anti-cleaved caspase 3 antibody. The number of cleaved caspase 3-positive cells was counted, and the data is shown as means ± SEM. These are representative data from experiments independently performed twice.

Original Research

28 February 2020

Myoblasts With Higher IRS-1 Levels Are Eliminated From the Normal Cell Layer During Differentiation

Ryosuke Okino

, 3 more and

Fumihiko Hakuno

3,498 views

2 citations