Controlled dimerization of insulin-like growth factor-1 and insulin receptors reveals shared and distinct activities of holo and hybrid receptors

Chen, Jingci; Nagle, Alison M.; Wang, Yufen; Boone, David N.; Lee, Adrian V.

doi:10.1074/jbc.m117.789503

Cited by 15 publications

(16 citation statements)

References 20 publications

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“…On one hand, IGF‐2R acts as a scavenger for circulating IGF‐2 and is not targeted by AG‐1024, whereas activation of IGF‐1R by IGF‐2 activates signaling leading to proliferation, survival and other downstream events . In addition, it was recently shown that proliferation is principally mediated by IGF‐1R as homodimers or as hybrid IGF‐1R/INSR receptors rather than through the INSR, and that prosurvival activity was mainly provided by homo IGF‐1R . Enhanced IGF‐1R signaling in CB CD34 + cells may be responsible for the enhanced expansion of PEP in OCM cultures.…”

Section: Discussionmentioning

confidence: 99%

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

et al. 2018

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Ex vivo expansion of hematopoietic stem cell (HSCs) and progenitors may one day overcome the slow platelet engraftment kinetics associated with umbilical cord blood transplantation. Serumfree medium conditioned with osteoblasts (i.e., osteoblast-conditioned medium [OCM]) derived from mesenchymal stromal cells (MSC) was previously shown to increase cell growth and raise the levels of human platelets in mice transplanted with OCM-expanded progenitors. Herein, we characterized the cellular and molecular mechanisms responsible for these osteoblast-derived properties. Limiting dilution transplantation assays revealed that osteoblasts secrete soluble factors that synergize with exogenously added cytokines to promote the production of progenitors with short-term platelet engraftment activities, and to a lesser extent with long-term platelet engraftment activities. OCM also modulated the expression repertoire of cell-surface receptors implicated in the trafficking of HSC and progenitors to the bone marrow. Furthermore, OCM contains growth factors with prosurvival and proliferation activities that synergized with stem cell factor. Insulin-like growth factor (IGF)-2 was found to be present at higher levels in OCM than in control medium conditioned with MSC. Inhibition of the IGF-1 receptor, which conveys IGF-2 0 intracellular signaling, largely abolished the growth-promoting activity of OCM on immature CD34 + subsets and progenitors in OCM cultures. Finally, IGF-1R effects appear to be mediated in part by the coactivator β-catenin. In summary, these results provide new insights into the paracrine regulatory activities of osteoblasts on HSC, and how these can be used to modulate the engraftment properties of human HSC and progenitors expanded in culture. STEM CELLS 2019;37:345-356 SIGNIFICANCE STATEMENTOsteoblasts are one of many different cell type implicated in the regulation of hematopoiesis through various mechanism including the release of paracrine factors such as growth factors, chemokines and extracellular matrix proteins. It has been shown that these factors strongly modulate the growth of umbilical cord blood stem and progenitor cells through activation of insulin-like growth factor-1 receptor and subsequent activation of the transcriptional activation complex β-catenin/TCF. Osteoblasts also modulated the expression repertoire of cell-surface receptors implicated in the homing of progenitors to the bone marrow. Altogether, these properties significantly enhanced the platelet engrafting activity of progenitors produced in cultures.

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Section: Discussionmentioning

confidence: 99%

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

et al. 2018

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“…Recently, Chen et al researched on the insulin receptor pathway and were able to differentiate between the insulin receptor types of the insulin-like growth factor receptor 1 (IGF1R) and the insulin receptor (InsR) as well as the respective hybrid of the heterodimer of both (HybR). The bivalent homodimerizer AP20187 and the heterodimerizer AP21967 were used as CIDs (Chen et al, 2018).…”

Section: Chemical Tools/chemically Induced Dimerization Utilizing Fkbpsmentioning

confidence: 99%

FKBP Ligands—Where We Are and Where to Go?

et al. 2018

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In recent years, many members of the FK506-binding protein (FKBP) family were increasingly linked to various diseases. The binding domain of FKBPs differs only in a few amino acid residues, but their biological roles are versatile. High-affinity ligands with selectivity between close homologs are scarce. This review will give an overview of the most prominent ligands developed for FKBPs and highlight a perspective for future developments. More precisely, human FKBPs and correlated diseases will be discussed as well as microbial FKBPs in the context of anti-bacterial and anti-fungal therapeutics. The last section gives insights into high-affinity ligands as chemical tools and dimerizers.

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“…Both IR-A/IGF-IR (Hybrid A) as well IR-B/IGF-IR (Hybrid B) receptors can be formed [ 27 ]. The biological functions of these hybrids remain uncertain without examining cells not expressing holo-IGF-IR or holo-IR [ 28 ]. Nevertheless, it has been suggested that IR/IGF-IR hybrids act in a manner similar to that of IGF-IR.…”

Section: Biology Of Insulin-like Growth Factor (Igf) Family and Thmentioning

confidence: 99%

“…Nevertheless, it has been suggested that IR/IGF-IR hybrids act in a manner similar to that of IGF-IR. Hybrid receptors respond more predictably to IGF-I than to insulin under physiological conditions [ 28 , 29 ]. They may account, at least in part, for the overlapping yet distinct actions of the two ligands.…”

Section: Biology Of Insulin-like Growth Factor (Igf) Family and Thmentioning

confidence: 99%

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Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

Janssen¹,

Smith

2021

Cells

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Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves’ disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves’ disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.

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Controlled dimerization of insulin-like growth factor-1 and insulin receptors reveals shared and distinct activities of holo and hybrid receptors

Abstract: Breast cancer development and progression is

Cited by 15 publications

References 20 publications

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties

FKBP Ligands—Where We Are and Where to Go?

Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

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