TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

Vázquez-Carballo, Ana; Ceperuelo-Mallafré, Victòria; Chacón, Matilde R.; Maymó-Masip, Elsa; Lorenzo, Margarita; Porrás, Almudena; Vendrell, Joan; Fernández‐Veledo, Sonia

doi:10.1152/ajpendo.00589.2012

Cited by 23 publications

(23 citation statements)

References 54 publications

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“…For the JNK pathway, Ser/Thr phosphatases may act as negative regulators, but little is known about those phosphatases specifically targeting the upper tiers of MAP3K or MAP2K enzymes. The PP5 and PP2A-type phosphatases, known as ERK MAPK pathway regulators, are potential candidates for this role (48,53,(63)(64)(65)(66)(67)(68). For JNKs themselves, dual Thr and Tyr phosphorylation within the JNK activation loop TPY motif is required for full JNK activity; thus, the removal of either phosphate can decrease JNK activity toward all substrates.…”

Section: Phosphatases and Feedback Mechanisms In Control Of Jnk Activitymentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

409

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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Section: Phosphatases and Feedback Mechanisms In Control Of Jnk Activitymentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

409

350

View full text Add to dashboard Cite

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“…(85). In both human and murine adipocytes, signaling through TNFR1 appears to have the largest contribution to insulin resistance (55,90). Adipose tissue macrophages (ATMs) produce the majority of TNF␣ in adipose tissue (93).…”

Section: Tumor Necrosis Factor-␣-stimulated Lipolysismentioning

confidence: 99%

Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis

Grant

Stephens

2015

American Journal of Physiology-Endocrinology and Metabolism

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Adipose tissue has the largest capacity to store energy in the body and provides energy through the release of free fatty acids during times of energy need. Different types of immune cells are recruited to adipose tissue under various physiological conditions, indicating that these cells contribute to the regulation of adipose tissue. One major pathway influenced by a number of immune cells is the release of free fatty acids through lipolysis during both physiological (e.g., cold stress) and pathophysiological processes (e.g., obesity, type 2 diabetes). Adipose tissue expansion during obesity leads to immune cell infiltration and adipose tissue remodeling, a homeostatic process that promotes inflammation in adipose tissue. The release of proinflammatory cytokines stimulates lipolysis and causes insulin resistance, leading to adipose tissue dysfunction and systemic disruptions of metabolism. This review focuses on the interactions of cytokines and other inflammatory molecules that regulate adipose tissue lipolysis during physiological and pathophysiological states.

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“…It is noteworthy that initial evidence supports not only inhibition of TWEAK/Fn14 as a potential therapeutic option, but also exogenous Fn14 stimulation, e.g., to protect neurons, to antagonize TNF-induced insulin resistance or to improve regeneration of β-cells or liver regeneration. [16][17][18][19] Based on the isolation of Fn14-specific camelid-derived antibodies, we describe here the development of chimeric mouse-human cross-reactive Fn14-specific IgG1 monoclonal antibodies (mAbs) that efficiently block TWEAK-induced Fn14 signaling. Like other Fn14-targeting antibodies, our novel llama antibodies convert into highly active Fn14 agonists upon oligomerization or Fcγ receptor (FcγR) binding.…”

Section: A Novel Llama Antibody Targeting Fn14 Exhibits Anti-metastatmentioning

confidence: 99%

A novel llama antibody targeting Fn14 exhibits anti-metastatic activity in vivo

Trebing

Lang

Chopra

et al. 2013

mAbs

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TWEAK prevents TNF-α-induced insulin resistance through PP2A activation in human adipocytes

Abstract: Vázquez-Carballo A, Ceperuelo-Mallafré V, Chacón MR, Maymó-Masip E, Lorenzo M, Porras A, Vendrell J, Fernández-Veledo S. TWEAK prevents TNF-␣-induced insulin resistance through PP2A activation in human adipocytes.

Cited by 23 publications

References 54 publications

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis

A novel llama antibody targeting Fn14 exhibits anti-metastatic activity in vivo

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