Understanding the mechanism of bias signaling of the insulin-like growth factor 1 receptor: Effects of LL37 and HASF

Bareja, Akshay; Patel, Shubham; Hodgkinson, Conrad P.; Payne, Alan; Dzau, Victor J.

doi:10.1016/j.cellsig.2018.02.013

Cited by 12 publications

(5 citation statements)

References 28 publications

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“…For example, stimulating FGFR2 and EGFR with their cognate ligands regulates distinct cellular outcomes like cell migration, cell proliferation, or cell survival (Francavilla et al, 2013;Francavilla et al, 2016;Watson et al, 2022). This biased signalling due to the binding of distinct ligands to the same receptor was also observed in other RTKs, such as in Insulin receptor family (Bareja et al, 2018). Also different isoforms of ligands can differentially regulate cell signalling, as shown for the two FGF8 isoforms FGF8a and FGF8b, which induces proliferation and differentiation, respectively (Sato and Nakamura, 2004).…”

Section: Ligand Identitymentioning

confidence: 89%

Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs

Samad,

Schwartz,

Francavilla

2024

Front. Cell Dev. Biol.

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Functional selectivity refers to the activation of differential signalling and cellular outputs downstream of the same membrane-bound receptor when activated by two or more different ligands. Functional selectivity has been described and extensively studied for G-protein Coupled Receptors (GPCRs), leading to specific therapeutic options for dysregulated GPCRs functions. However, studies regarding the functional selectivity of Receptor Tyrosine Kinases (RTKs) remain sparse. Here, we will summarize recent data about RTK functional selectivity focusing on how the nature and the amount of RTK ligands and the crosstalk of RTKs with other membrane proteins regulate the specificity of RTK signalling. In addition, we will discuss how structural changes in RTKs upon ligand binding affects selective signalling pathways. Much remains to be known about the integration of different signals affecting RTK signalling specificity to orchestrate long-term cellular outcomes. Recent advancements in omics, specifically quantitative phosphoproteomics, and in systems biology methods to study, model and integrate different types of large-scale omics data have increased our ability to compare several signals affecting RTK functional selectivity in a global, system-wide fashion. We will discuss how such methods facilitate the exploration of important signalling hubs and enable data-driven predictions aiming at improving the efficacy of therapeutics for diseases like cancer, where redundant RTK signalling pathways often compromise treatment efficacy.

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Section: Ligand Identitymentioning

confidence: 89%

Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs

Samad,

Schwartz,

Francavilla

2024

Front. Cell Dev. Biol.

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“… 549 , 550 Secreted hypoxia- and Akt-induced stem cell factor (HASF) could activate the IGF-1 receptor, stimulate cardiomyocyte proliferation, and inhibit apoptosis. 551 – 554 sFRP2 inhibited the Wnt pathway and apoptosis and protected the heart during myocardial infarction. 555 Some paracrine factors could protect the heart by modulating metabolism.…”

Section: Emerging Therapeutic Strategies For Failing Heartmentioning

confidence: 97%

Signaling cascades in the failing heart and emerging therapeutic strategies

Long

et al. 2022

Sig Transduct Target Ther

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Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein–protein, protein–RNA, and RNA–RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.

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“…Further, GPCRs can utilize receptor tyrosine kinases (RTKs) to mediate important cellular responses, such as proliferation, differentiation, and survival [ 8 ]. Depending on the receptor and cell type, GPCRs signaling involves transactivation of several different RTKs, such as insulin-like growth factor 1 receptor (IGF1R), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR) [ 9 , 10 , 11 ]. Then, numerous growth factors use G proteins and associated signaling molecules that participate downstream of RTKs to signal to effectors.…”

Section: Structure and Signal Transduction Of G Protein-coupled Rementioning

confidence: 99%

Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma

Peng

Sun

et al. 2018

IJMS

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Among a great variety of cell surface receptors, the largest superfamily is G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors. GPCRs can modulate diverse signal-transduction pathways through G protein-dependent or independent pathways which involve β-arrestins, G protein receptor kinases (GRKs), ion channels, or Src kinases under physiological and pathological conditions. Recent studies have revealed the crucial role of GPCRs in the tumorigenesis and the development of cancer metastasis. We will sum up the functions of GPCRs—particularly those coupled to chemokines, prostaglandin, lysophosphatidic acid, endothelin, catecholamine, and angiotensin—in the proliferation, invasion, metastasis, and angiogenesis of hepatoma cells and the development of hepatocellular carcinoma (HCC) in this review. We also highlight the potential avenues of GPCR-based therapeutics for HCC.

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Understanding the mechanism of bias signaling of the insulin-like growth factor 1 receptor: Effects of LL37 and HASF

Cited by 12 publications

References 28 publications

Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs

Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs

Signaling cascades in the failing heart and emerging therapeutic strategies

Emerging Roles of G Protein-Coupled Receptors in Hepatocellular Carcinoma

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