International Journal of Molecular Sciences

Research

Jump to: Review

29 pages, 11474 KiB

Open AccessArticle

Asynchronous Pattern of MAPKs’ Activity during Aging of Different Tissues and of Distinct Types of Skeletal Muscle

by Nechama Gilad, Manju Payini Mohanam, Ilona Darlyuk-Saadon, C. K. Matthew Heng, Inbar Plaschkes, Hadar Benyamini, Nikolay V. Berezhnoy and David Engelberg

Int. J. Mol. Sci. 2024, 25(3), 1713; https://doi.org/10.3390/ijms25031713 - 30 Jan 2024

Viewed by 713

Abstract

The MAPK p38α was proposed to be a prominent promoter of skeletal muscle aging. The skeletal muscle tissue is composed of various muscle types, and it is not known if p38α is associated with aging in all of them. It is also not [...] Read more.

The MAPK p38α was proposed to be a prominent promoter of skeletal muscle aging. The skeletal muscle tissue is composed of various muscle types, and it is not known if p38α is associated with aging in all of them. It is also not known if p38α is associated with aging of other tissues. JNK and ERK were also proposed to be associated with aging of several tissues. Nevertheless, the pattern of p38α, JNK, and ERK activity during aging was not documented. Here, we documented the levels of phosphorylated/active p38α, Erk1/2, and JNKs in several organs as well as the soleus, tibialis anterior, quadriceps, gastrocnemius, and EDL muscles of 1-, 3-, 6-, 13-, 18-, and 24-month-old mice. We report that in most tissues and skeletal muscles, the MAPKs’ activity does not change in the course of aging. In most tissues and muscles, p38α is in fact active at younger ages. The quadriceps and the lungs are exceptions, where p38α is significantly active only in mice 13 months old or older. Curiously, levels of active JNK and ERKs are also elevated in aged lungs and quadriceps. RNA-seq analysis of the quadriceps during aging revealed downregulation of proteins related to the extra-cellular matrix (ECM) and ERK signaling. A panel of mRNAs encoding cell cycle inhibitors and senescence-associated proteins, considered to be aging markers, was not found to be elevated. It seems that the pattern of MAPKs’ activation in aging, as well as expression of known ‘aging’ components, are tissue- and muscle type-specific, supporting a notion that the process of aging is tissue- and even cell-specific. Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

20 pages, 3252 KiB

Open AccessArticle

Differential Modulation of the Phosphoproteome by the MAP Kinases Isoforms p38α and p38β

by Dganit Melamed Kadosh, Jonah Beenstock, David Engelberg and Arie Admon

Int. J. Mol. Sci. 2023, 24(15), 12442; https://doi.org/10.3390/ijms241512442 - 04 Aug 2023

Cited by 1 | Viewed by 992

Abstract

The p38 members of the mitogen-activated protein kinases (MAPKs) family mediate various cellular responses to stress conditions, inflammatory signals, and differentiation factors. They are constitutively active in chronic inflammatory diseases and some cancers. The differences between their transient effects in response to signals [...] Read more.

The p38 members of the mitogen-activated protein kinases (MAPKs) family mediate various cellular responses to stress conditions, inflammatory signals, and differentiation factors. They are constitutively active in chronic inflammatory diseases and some cancers. The differences between their transient effects in response to signals and the chronic effect in diseases are not known. The family is composed of four isoforms, of which p38α seems to be abnormally activated in diseases. p38α and p38β are almost identical in sequence, structure, and biochemical and pharmacological properties, and the specific unique effects of each of them, if any, have not yet been revealed. This study aimed to reveal the specific effects induced by p38α and p38β, both when transiently activated in response to stress and when chronically active. This was achieved via large-scale proteomics and phosphoproteomics analyses using stable isotope labeling of two experimental systems: one, mouse embryonic fibroblasts (MEFs) deficient in each of these p38 kinases and harboring either an empty vector or vectors expressing p38α^WT, p38β^WT, or intrinsically active variants of these MAPKs; second, induction of transient stress by exposure of MEFs, p38α^−/−, and p38β^−/− MEFs to anisomycin. Significant differences in the repertoire of the proteome and phosphoproteome between cells expressing active p38α and p38β suggest distinct roles for each kinase. Interestingly, in both cases, the constitutive activation induced adaptations of the cells to the chronic activity so that known substrates of p38 were downregulated. Within the dramatic effect of p38s on the proteome and phosphoproteome, some interesting affected phosphorylation sites were those found in cancer-associated p53 and Hspb1 (HSP27) proteins and in cytoskeleton-associated proteins. Among these, was the stronger direct phosphorylation by p38α of p53-Ser309, which was validated on the Ser315 in human p53. In summary, this study sheds new light on the differences between chronic and transient p38α and p38β signaling and on the specific targets of these two kinases. Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 1156 KiB

Open AccessReview

The IGF1 Signaling Pathway: From Basic Concepts to Therapeutic Opportunities

by Haim Werner

Int. J. Mol. Sci. 2023, 24(19), 14882; https://doi.org/10.3390/ijms241914882 - 04 Oct 2023

Cited by 6 | Viewed by 2042

Abstract

Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface protein that is evolutionarily related to the insulin [...] Read more.

Insulin-like growth factor 1 (IGF1) is a peptide growth factor with important functions in multiple aspects of growth, development and metabolism. The biological actions of IGF1 are mediated by the IGF1 receptor (IGF1R), a cell-surface protein that is evolutionarily related to the insulin receptor (InsR). The effects of IGF1 are moderated by a group of binding proteins (IGFBPs) that bind and transport the ligand in the circulation and extracellular fluids. In mechanistic terms, IGF1R function is linked to the MAPK and PI3K signaling pathways. Furthermore, IGF1R has been shown to migrate to cell nucleus, where it functions as a transcriptional activator. The co-localization of IGF1R and MAPK in the nucleus is of major interest as it suggests novel mechanistic paradigms for the IGF1R-MAPK network. Given its potent anti-apoptotic and pro-survival roles, and in view of its almost universal pattern of expression in most types of cancer, IGF1R has emerged as a promising molecular target in oncology. The present review article provides a concise overview of key scientific developments in the research area of IGF and highlights a number of more recent findings, including its nuclear migration and its interaction with oncogenes and tumor suppressors. Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

17 pages, 1841 KiB

Open AccessReview

Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2

by Wenjing Chen and Jong-In Park

Int. J. Mol. Sci. 2023, 24(19), 14837; https://doi.org/10.3390/ijms241914837 - 02 Oct 2023

Cited by 2 | Viewed by 1448

Abstract

BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK [...] Read more.

BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information. Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

18 pages, 1123 KiB

Open AccessReview

Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy

by Elke Burgermeister

Int. J. Mol. Sci. 2023, 24(19), 14546; https://doi.org/10.3390/ijms241914546 - 26 Sep 2023

Cited by 1 | Viewed by 1310

Abstract

The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These ligand-activated transcription factors are divided into subclasses comprising receptors for endocrine hormones, metabolic compounds (e.g., vitamins, diet), xenobiotics, and mediators released [...] Read more.

The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These ligand-activated transcription factors are divided into subclasses comprising receptors for endocrine hormones, metabolic compounds (e.g., vitamins, diet), xenobiotics, and mediators released from host immune reactions such as tissue injury and inflammation. These internal and external cues place the NRSF at the frontline as sensors and translators of information from the environment towards the genome. For most of the former “orphan” receptors, physiological and synthetic ligands have been identified, opening intriguing opportunities for combination therapies with existing cancer medications. Hitherto, only preclinical data are available, warranting further validation in clinical trials in patients. The current review summarized the existing literature covering the expression and function of NRSF subclasses in human solid tumors and hematopoietic malignancies and their modulatory effects on innate (e.g., macrophages, dendritic cells) and adaptive (i.e., T cell subsets) immune cells, encouraging mechanistic and pharmacological studies in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1). Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

30 pages, 961 KiB

Open AccessReview

Mitogen-Activated Protein Kinase and Nuclear Hormone Receptor Crosstalk in Cancer Immunotherapy

by Elke Burgermeister

Int. J. Mol. Sci. 2023, 24(17), 13661; https://doi.org/10.3390/ijms241713661 - 04 Sep 2023

Viewed by 1404

Abstract

The three major MAP-kinase (MAPK) pathways, ERK1/2, p38 and JNK/SAPK, are upstream regulators of the nuclear “hormone” receptor superfamily (NHRSF), with a prime example given by the estrogen receptor in breast cancer. These ligand-activated transcription factors exert non-genomic and genomic functions, where they [...] Read more.

The three major MAP-kinase (MAPK) pathways, ERK1/2, p38 and JNK/SAPK, are upstream regulators of the nuclear “hormone” receptor superfamily (NHRSF), with a prime example given by the estrogen receptor in breast cancer. These ligand-activated transcription factors exert non-genomic and genomic functions, where they are either post-translationally modified by phosphorylation or directly interact with components of the MAPK pathways, events that govern their transcriptional activity towards target genes involved in cell differentiation, proliferation, metabolism and host immunity. This molecular crosstalk takes place not only in normal epithelial or tumor cells, but also in a plethora of immune cells from the adaptive and innate immune system in the tumor–stroma tissue microenvironment. Thus, the drugability of both the MAPK and the NHRSF pathways suggests potential for intervention therapies, especially for cancer immunotherapy. This review summarizes the existing literature covering the expression and function of NHRSF subclasses in human tumors, both solid and leukemias, and their effects in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1). Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

18 pages, 1071 KiB

Open AccessReview

JNK Cascade-Induced Apoptosis—A Unique Role in GqPCR Signaling

by Guy Nadel, Galia Maik-Rachline and Rony Seger

Int. J. Mol. Sci. 2023, 24(17), 13527; https://doi.org/10.3390/ijms241713527 - 31 Aug 2023

Cited by 1 | Viewed by 1069

Abstract

The response of cells to extracellular signals is mediated by a variety of intracellular signaling pathways that determine stimulus-dependent cell fates. One such pathway is the cJun-N-terminal Kinase (JNK) cascade, which is mainly involved in stress-related processes. The cascade transmits its signals via [...] Read more.

The response of cells to extracellular signals is mediated by a variety of intracellular signaling pathways that determine stimulus-dependent cell fates. One such pathway is the cJun-N-terminal Kinase (JNK) cascade, which is mainly involved in stress-related processes. The cascade transmits its signals via a sequential activation of protein kinases, organized into three to five tiers. Proper regulation is essential for securing a proper cell fate after stimulation, and the mechanisms that regulate this cascade may involve the following: (1) Activatory or inhibitory phosphorylations, which induce or abolish signal transmission. (2) Regulatory dephosphorylation by various phosphatases. (3) Scaffold proteins that bring distinct components of the cascade in close proximity to each other. (4) Dynamic change of subcellular localization of the cascade’s components. (5) Degradation of some of the components. In this review, we cover these regulatory mechanisms and emphasize the mechanism by which the JNK cascade transmits apoptotic signals. We also describe the newly discovered PP2A switch, which is an important mechanism for JNK activation that induces apoptosis downstream of the Gq protein coupled receptors. Since the JNK cascade is involved in many cellular processes that determine cell fate, addressing its regulatory mechanisms might reveal new ways to treat JNK-dependent pathologies. Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

23 pages, 2329 KiB

Open AccessReview

Mitogen-Activated Protein Kinases (MAPKs) and Enteric Bacterial Pathogens: A Complex Interplay

by Ipsita Nandi and Benjamin Aroeti

Int. J. Mol. Sci. 2023, 24(15), 11905; https://doi.org/10.3390/ijms241511905 - 25 Jul 2023

Cited by 2 | Viewed by 1992

Abstract

Diverse extracellular and intracellular cues activate mammalian mitogen-activated protein kinases (MAPKs). Canonically, the activation starts at cell surface receptors and continues via intracellular MAPK components, acting in the host cell nucleus as activators of transcriptional programs to regulate various cellular activities, including proinflammatory [...] Read more.

Diverse extracellular and intracellular cues activate mammalian mitogen-activated protein kinases (MAPKs). Canonically, the activation starts at cell surface receptors and continues via intracellular MAPK components, acting in the host cell nucleus as activators of transcriptional programs to regulate various cellular activities, including proinflammatory responses against bacterial pathogens. For instance, binding host pattern recognition receptors (PRRs) on the surface of intestinal epithelial cells to bacterial pathogen external components trigger the MAPK/NF-κB signaling cascade, eliciting cytokine production. This results in an innate immune response that can eliminate the bacterial pathogen. However, enteric bacterial pathogens evolved sophisticated mechanisms that interfere with such a response by delivering virulent proteins, termed effectors, and toxins into the host cells. These proteins act in numerous ways to inactivate or activate critical components of the MAPK signaling cascades and innate immunity. The consequence of such activities could lead to successful bacterial colonization, dissemination, and pathogenicity. This article will review enteric bacterial pathogens’ strategies to modulate MAPKs and host responses. It will also discuss findings attempting to develop anti-microbial treatments by targeting MAPKs. Full article

(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases)

► Show Figures

Figure 1

Journal Menu

Journal Browser

MAPK Signaling Cascades in Human Health and Diseases

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Related Special Issue

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI