Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

Torrente, Yvan; Bella, Pamela; Tripodi, Luana; Villa, Chiara; Farini, Andrea

doi:10.3390/cells9020441

Cited by 32 publications

(20 citation statements)

References 88 publications

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“…While IGF2R lacks intrinsic kinase activity and acts as a scavenger of extracellular IGF2 [ 13 ], the IRR has been long viewed as an orphan receptor but recent data have demonstrated that the IRR acts as an extracellular Alkali Sensor [ 2 , 14 ].…”

Section: The Igf System: Receptors Ligands and Binding Proteinsmentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

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The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.

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Section: The Igf System: Receptors Ligands and Binding Proteinsmentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

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“…A previous study showed that Igf-2 up-regulates its own gene expression via the Akt/PKB pathway (35). Elevation of Igf-2 mRNA was found in C2 myoblasts after 24 hours' culture in differentiation medium containing 2-10% horse serum (36), while Erbay et al (2003) suggested that mTOR regulates Igf-2 production at the transcriptional level when cultured under low mitogen conditions (37,38). There has also been a study suggesting that myoblasts under low mitogen conditions have elevated levels of IGFBP5, which helps concentrate IGF-2 to a threshold level which triggers the IGF-1R pathway leading to differentiation (39,40).…”

Section: Dystrophin-de Cient Myoblasts Do Not Achieve Terminal Differmentioning

confidence: 99%

Perturbation of PI3K/Akt Signaling Affected Autophagy Modulation in Dystrophin-deficient Myoblasts

Yazid

Chen

2020

Preprint

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Background: The absence of dystrophin has gave a massive impact on myotube development in Muscular Dystrophy pathogenesis. One of the conserved signaling pathways involved in skeletal muscle differentiation is the PI3K/Akt/mTOR pathway that plays a vital role in autophagy regulation. To further understand and establish targeted therapy in dystrophin-deficient myoblasts, protein expression profiling has been determined which provides information on perturbed autophagy modulation and activation. Methods: In this study, a dystrophin-deficient myoblast cell line established from the skeletal muscle of a dystrophic (mdx) mouse was used as a model. The dfd13 (dystrophin-deficient) and C2C12 (non-dystrophic) myoblasts were cultured in low mitogen conditions for 10 days to induce differentiation. The cells were subjected to total protein extraction prior to Western blotting assay technique. Protein sub-fractionation has been conducted to determine protein localization. The live-cell analysis of autophagy assay was done using a flow cytometer. Results: In our culture system, the dfd13 myoblasts did not achieve terminal differentiation. PTEN expression was profoundly increased in dfd13 myoblasts throughout the differentiation day subsequently indicates perturbation of PI3K/Akt/mTOR regulation. In addition, rictor-mTORC2 was also found inactivated in this event. This occurrence has caused FoxO3 misregulation leads to higher activation of autophagy-related genes in dfd13 myoblasts. Autophagosome formation was increased as LC3B-I/II showed accumulation upon differentiation. However, the ratio of LC3B lipidation and autophagic flux were shown decreased which exhibited dystrophic features. Conclusion: perturbation of the PTEN-PI3K/Akt pathway triggers excessive autophagosome formation and subsequently reduced autophagic flux within dystrophin-deficient myoblasts where these findings are of importance to understand Duchenne Muscular Dystrophy (DMD) patients. We believe that some manipulation within its regulatory signaling reported in this study could help restore muscle homeostasis and attenuate disease progression.

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“…The other two receptors of the family are the IGF2R and IRR. The IGF2R is a type-1 transmembrane glycoprotein which lacks intrinsic kinase activity and acts by scavenging extracellular IGF2, thus titrating IGF2 levels and suppressing IGF signaling [22]. On the other hand, little is known about the IRR, despite the close homology with the IGF1R and IR.…”

Section: The Igf System: Major Components and Signal Transductionmentioning

confidence: 99%

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

Mancarella

Morrione

Scotlandi

2021

Cells

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Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.

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Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

Cited by 32 publications

References 88 publications

Novel Regulators of the IGF System in Cancer

Novel Regulators of the IGF System in Cancer

Perturbation of PI3K/Akt Signaling Affected Autophagy Modulation in Dystrophin-deficient Myoblasts

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

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Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

Cited by 32 publications

References 88 publications

Novel Regulators of the IGF System in Cancer

Novel Regulators of the IGF System in Cancer

Perturbation of PI3K/Akt&nbsp;Signaling Affected Autophagy Modulation in Dystrophin-deficient Myoblasts

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

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Perturbation of PI3K/Akt Signaling Affected Autophagy Modulation in Dystrophin-deficient Myoblasts