Mitsugumin 53 (MG53) Ligase Ubiquitinates Focal Adhesion Kinase during Skeletal Myogenesis

Nguyen, Nga; Yi, Jae Sung; Park, Heonyong; Lee, Jae Seon; Ko, Young Gyu

doi:10.1074/jbc.m113.525154

Cited by 49 publications

(66 citation statements)

References 27 publications

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“…A previous study has demonstrated that Cat.G, a neutrophil-derived serine protease, induces ubiquitin-proteasome-dependent degradation of FAK (14). Inhibition of proteasome activity markedly attenuates FAK degradation in T-, myofibril and ovarian carcinoma cells (14,20,21). In the present study, trypsin induced the mono-ubiquitination of FAK in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 52%

“…Results from previous studies have revealed that MG53, an E3 ubiquitin ligase, mediates FAK ubiquitination during skeletal myogenesis (21), and that c-Cbl is involved in FAK degradation thereby suppressing cell adhesion and myocyte survival (14). Cbl-b, a negative regulator of non-receptor tyrosine kinases, may cause FAK ubiquitination and degradation.…”

Section: Discussionmentioning

confidence: 99%

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Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Fan

et al. 2016

Oncology Letters

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Abstract. Cancer cell detachment from the primary tumor site represents the first stage of metastasis. Previous studies have identified that cell detachment is triggered by cytoskeletal disruption, which may induce a wide variety of cellular changes. Focal adhesion kinase (FAK) exhibits crucial cellular functions, including regulation of the cytoskeleton. These observations have provided exciting insights into the effect of FAK in cell detachment; however, the involvement of FAK in cell detachment remains controversial. The aim of the present study was to evaluate the effect of FAK and its function in the process of cell detachment. The results revealed that FAK expression was downregulated following trypsin treatment in human gastric, lung, colon and breast cancer cell lines, as well as a human gastric epithelial cell line. Knockdown of FAK enhanced cell detachment in gastric cancer MGC803 cells, indicating that FAK inhibits cell detachment. Further investigation revealed that trypsin induced monoubiquitination of FAK. In addition, the lysosome inhibitor, NH 4 Cl, decreased trypsin-induced degradation of FAK. Casitas B-lineage lymphoma-b (Cbl-b), an E3 ubiquitin ligase, was involved in this process, which interacted with FAK, as demonstrated by co-precipitation experiments, and promoted trypsin-induced ubiquitin-lysosome degradation of FAK. These results indicate that Cbl-b promotes cell detachment via ubiquitination of FAK. These findings provide novel insights regarding the effect of FAK and Cbl-b in the process of cancer cell detachment.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Fan

et al. 2016

Oncology Letters

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“…Trim72, a muscle-specific E3 ligase that targets proteins near the membrane following oxidative stress, regulates FAK expression by ubiquitination and proteosomal degradation. 25 Our data excludes upregulation of this gene as a mechanism underlying the decreases in FAK expression at 56 days post SCI. The numerical though nonsignificant increase in the 41 kDa C-terminal portion of FAK following SCI suggests that full-length FAK is being cleaved into the inhibitory protein FRNK by an unknown mechanism, although there is a possibility that there is an increase of transcription and translation of FRNK through alternative splicing of FAK mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…The E3 ubiquitin ligase Trim72 (also known as mitsugumin 53) ubiquitinates FAK and targets it for proteolytic destruction. 25 Trim72 mRNA and protein levels were, however, not changed at 56 days after SCI (Figure 6b; P40.050).…”

Section: Caspase-3/7 Activity and Trim72mentioning

confidence: 99%

Focal adhesion kinase signaling is decreased 56 days following spinal cord injury in rat gastrocnemius

et al. 2015

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Study design: Descriptive study. Objectives: The goal of this study was to determine the effects of spinal cord injury (SCI) on aspects of the focal adhesion kinase (FAK) signaling pathway 56 days post injury in rat gastrocnemius. Setting: This study was conducted in Bronx, NY, USA. Methods: Three-month-old male Wistar rats were exposed to either a sham surgery (n = 10) or complete T4 spinal cord transection (n = 10). Rats were killed 56 days following surgery and the muscle was collected. Following homogenization, proteins of the FAK pathway were analyzed by western immunoblotting or reverse transcription-qPCR. In addition, cellular markers for proteins that target the degradation of FAK were investigated. Results: SCI resulted in significantly lower levels of total and phosphorylated FAK, cSrc and p70S6k, and a trend for increased FRNK protein expression. SCI did not change levels of the α7 or β1 integrin subunits, total or phosphorylated ERK1/2, phosphorylated Akt and TSC2 or total p70S6k. SCI resulted in a greater expression of total Akt. mRNA expression of FAK and the α7 or β1 integrins remained unchanged between sham and SCI groups. Caspase-3/7 activity and Trim72 mRNA and protein expression remained unchanged following SCI. Conclusion: SCI results in diminished FAK signaling and is independent of ERK1/2 and Akt. SCI has no effect on mRNA levels for genes encoding components of the focal adhesion 56 days after injury.

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“…Loss of Trim72 function promotes myogenesis (55) through its ability to modulate fusion and myogenin expression. It can target the focal adhesion kinase FAK for degradation (77), and FAK has been observed to promote the expression of the profusion genes caveolin-3 and ␤1D-integrin (86) as well as myogenin (61).…”

Section: The Ups Regulates Myogenesismentioning

confidence: 99%

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

Bilodeau

Coyne

Wing

2016

American Journal of Physiology-Cell Physiology

136

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Bilodeau PA, Coyne ES, Wing SS. The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am J Physiol Cell Physiol 311: C392-C403, 2016. First published August 10, 2016; doi:10.1152/ajpcell.00125.2016.-Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3␤, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.hormones; muscle atrophy SKELETAL MUSCLE SERVES TWO essential functions, a contractile function for locomotion/maintenance of posture and a metabolic function as the protein reservoir of the body. The myofibers that make up the muscle consist primarily of myofibrillar proteins. The ability of the body to maintain posture or to move arises from the precise organization of myofibrillar proteins into a contractile unit called the sarcomere. The sarcomere consists of thick filaments containing primarily myosin that can slide over thin filaments containing primarily actin. Both types of filaments contain additional regulatory proteins and are linked to the ␣-actinin-containing Z disk, the thin filaments directly so and the thick filaments via titin. Vimentin and desmin are intermediate filaments that serve to anchor sarcomeres properly at the Z disks. These myofibrillar proteins, as well as the sarcoplasmic proteins, also serve as the protein reservoir of the body. Upon fasting, once hepatic glycogen stores are depleted, muscle protein degradation must be activated to provide amino acids to the liver for gluconeogenesis. These amino a...

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Mitsugumin 53 (MG53) Ligase Ubiquitinates Focal Adhesion Kinase during Skeletal Myogenesis

Cited by 49 publications

References 27 publications

Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Cbl-b promotes cell detachment via ubiquitination of focal adhesion kinase

Focal adhesion kinase signaling is decreased 56 days following spinal cord injury in rat gastrocnemius

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

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